Open Access

Advances of HIF‑1α/glycolysis axis in non‑small cell lung cancer (Review)

  • Authors:
    • Yuxuan Shi
    • Xiangyi Lin
    • Jinwen Wang
    • Zhiqing Zhou
    • Sijie Chen
    • Guoan Chen
  • View Affiliations

  • Published online on: February 15, 2024     https://doi.org/10.3892/or.2024.8714
  • Article Number: 55
  • Copyright: © Shi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

It is now widely accepted that there is a specific metabolic pattern in tumor cells termed the Warburg effect, which causes tumor cells to tend to use glycolysis for energy. Hypoxia‑inducible factor (HIF) 1α is involved in these metabolic patterns as a key molecule promoting glycolysis. In addition, there is now increasing evidence that targeting this metabolic pattern of the tumor to cut off the energy source of the tumor tissue is an effective therapeutic modality. However, different molecules are involved in the regulation of the HIF‑1α/glycolysis axis in different tumor tissues. This review focused on non‑small cell lung cancer (NSCLC) to elucidate the currently known signaling pathways centered on the HIF‑1α/glycolysis axis and to identify the key molecules that can serve as therapeutic targets. It also summarized the effective methods of treatment of NSCLC by inhibition of HIF‑1α/glycolysis that have emerged in recent years.

Introduction

Lung cancer is considered being one of the most threatening malignant tumors in the health and life of individuals, with the highest fatality rate in the world (1). It can be histologically divided into two categories: Small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), of which NSCLC accounts for ~85% (2). NSCLC is characterized by lack of symptoms when tumors are small in the early stages, so most patients have locally advanced or metastatic lesions at diagnosis (3). Therefore, it is of great importance to understand the mechanism of NSCLC development to guide the development and use of lung cancer-targeted drugs, including the combination of clinical drugs.

In the past decade, scholars have generally recognized the importance of tumor-specific metabolic patterns in the pathogenesis of tumors. Among them, the Warburg effect indicates that tumor cells tend to obtain energy through aerobic glycolysis along with lactate production, even in the presence of oxygen (4). In addition, hypoxia is an important feature of solid tumors and induces cells to undergo glycolysis to produce energy (5). Therefore, efficient glycolysis is the main function of tumor cells. The occurrence of this phenomenon depends on the regulation of intracellular oncogene and tumor suppressor gene signaling pathways on cellular metabolic pathways. The central regulator in the above regulatory process is the hypoxia-inducible factor (HIF) (6).

HIF is a type of transcription factor that is rapidly produced and accumulated in the cell environment under hypoxic conditions. It was initially discovered that it can significantly increase the transcription of erythropoietin by interacting with its enhancer (7). HIF is a heterodimer consisting of one α-subunit and one β-subunit. It is currently known that there are three types of both a-subunit and β-subunit which are HIF-1α, HIF-2α, HIF-3α, HIF-1β, HIF-2β and HIF-3β (8). Among them, HIF-1α is the most oxygen-sensitive active subunit, which is the main part of HIF-1 to fulfill its function, and it is the earliest discovered and the more thoroughly studied subunit at present (9). Under physiological conditions when oxygen supply is sufficient, HIF-1α is easily degraded by the proteasome through the complex formed by oxygen-dependent hydroxylation and E3 ubiquitin ligase, so its half-life is only 5–10 min (10). As a result, signaling pathways downstream of HIF are not activated and transcription of the more than 40 genes it regulates, including erythropoietin, glucose transporter proteins, glycolytic enzymes, vascular endothelial growth factor and other genes and protein products that increase oxygen delivery or promote hypoxic metabolism, is at a low level (11).

Generally, regulation of HIF-1α expression is complex and can be categorized into oxygen-dependent and oxygen-independent components. The oxygen-independent mechanisms include the transcription regulation of HIF-1α expression through the action of transcription factors such as nuclear factor-κB (NF-κB), specificity protein 1 (SP1) and signal transducer and activator of transcription 3 (STAT3) (12). The actions of these transcription factors are in turn regulated by reactive oxygen species (ROS), cytokines and/or lipopolysaccharide (LPS)-dependent signaling-activated protein kinase C (PKC), NF-κB kinase inhibitor (IKK), and/or phosphatidylinositol 3-kinase (PI3K) pathways (13). HIF-1α protein translation can be regulated by microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and/or angiotensin II-mediated signaling involving PI3K. The oxygen-dependent mechanism affecting the half-life of HIF protein in the normal state is mainly due to the von Hippel-Lindau protein (pVHL) degradation pathway. In this degradation pathway, pVHL catalyzes the ubiquitination of the hydroxylated HIF-1α (14). While hydroxylation of the HIF-1α is catalyzed by two currently known enzymes, prolyl hydroxylase domain-containing proteins (PHDs) and asparagine hydroxylase factor inhibiting HIF (FIH) (15,16), their activity is reduced by a decrease in oxygen tension and thus the stability of the HIF-1α is affected by oxygen tension.

From the clinical data, HIF-1α is highly expressed in NSCLC and is strongly associated with poor clinical prognosis (1719). Therefore, studying the role of HIF-1α in NSCLC is of great significance for NSCLC treatment. The current review focused on HIF-1α mediated glycolysis in NSCLC, described the intracellular regulatory mechanisms and summarized how they affect the development and treatment of tumors.

Regulation of HIF-1α expression in NSCLC

A number of clinical investigations have shown that the positive rate of HIF-1α expression in NSCLC is significantly higher (up to 15–20 times) than that in normal tissues (2022). This phenomenon is closely related to the molecular signaling and cells in the tumor microenvironment described in the following sections.

Molecular signaling regulating HIF-1α level

Several molecules that are differentially expressed in NSCLC compared with normal cells can alter the HIF-1α expression in NSCLC by affecting the transcription, translation or protein degradation of HIF-1α (Fig. 1). In the HIF-1α protein degradation signaling pathway, it has been found that in primary NSCLC, the content of intracellular HIF-1α and the expression of its downstream genes are positively correlated with the expression of PHD protein family (23). Aldolase A is also highly expressed in NSCLC and is positively correlated with the expression of HIF-1α in the nucleus. It can cause HIF-1α accumulation by promoting the release of lactic acid, which causes the decrease in PHD activity (24). ROS can also inhibit PHD to stabilize HIF-1α (25) and the depletion of intracellular succinate dehydrogenase 5 in high glucose environment leads to the accumulation of ROS and the increase of HIF-1α protein level (26) (Fig. 1 left; bottom orange section).

The main factor on the transcriptional regulation of HIF-1α is STAT3 signaling pathway (Fig. 1 left; top green section) in NSCLC. The JAK2/STAT3 pathway is inhibited by miR-337-3p, which is downregulated in NSCLC. At the same time, circular (circ)RNA zinc finger protein 124 is highly expressed and binds with miR-337-3p to further weaken its inhibitory effect on JAK2/STAT3 pathway (27). In addition, Ras-related protein Rab-17 is downregulated in NSCLS, which could reduce the inhibition of STAT3 phosphorylation (28). The non-coding (nc)RNA TSLNC8 is also downregulated, which can inhibit the IL-6/STAT3 signaling pathway. Taken together, all these three signaling pathways can promote the transcription expression of HIF-1α via STAT3 pathway in NSCLC cells (29).

The translational regulation of HIF-1α is promoted by eukaryotic initiation factor 4G1(eIF4G1) and mTOR signaling pathways (Fig. 1 left; middle blue section). Eukaryotic initiation factor complex F4 (eIF4F) includes eIF4G1 and eIF4E. MET significantly increases the phosphorylation level on Ser-1232 of eIF4G1 via MAPK, which leads to the translational expression of HIF-1α (30). Activation of PI3K/AKT/mTOR pathway also promotes HIF-1α translation. Retinoblastoma binding protein 2 (RBP2) is highly expressed in NSCLC and is associated with poor prognosis. By stimulating this pathway, RBP2 can upregulate the expression of HIF-1α to promote the growth of tumor blood vessels (31).

Cells in tumor microenvironment affecting HIF-1α level

Several types of cells in the tumor cell microenvironment are also involved in the regulation of HIF-1α expression inside NSCLC (Fig. 1 right panel). Cancer-associated fibroblasts (CAFs) are important stromal cell components in the solid tumor microenvironment and significantly accelerate the proliferation, invasion and epithelial-mesenchymal transition of NSCLC cells (32). miR-224 is significantly upregulated in both CAFs and CAFs co-cultured NSCLC cells and Sirtuins 3 (SIRT3)/AMPK axis is inhibited by miR-224-targeted SIRT3 untranslated region in NSCLC, thereby activating mTOR and increasing HIF-1α expression. In turn, high levels of HIF-1α can promote the high expression of miR-224, forming a positive feedback loop (33). Mesenchymal stem cells (MSCs)-derived exosomal miR-204 acts on Krüppel-like factor 7 (KLF7) in NSCLC to downregulate the KLF7/AKT/mTOR/HIF-1α axis to play an anticancer role (34). M2 macrophage-derived extracellular vesicles regulate the Hippo/HIF-1 axis to enhance the cell viability and migration ability of NSCLC under hypoxic conditions (35).

Regulatory mechanism of HIF-1α/glycolysis axis in NSCLC

As HIF-1α is a transcription factor, its activation can promote the transcription of multiple genes, including energy metabolism, angiogenesis and apoptosis, among which glycolysis-related genes are the most important in NSCLC. The currently known ways in which HIF-1α promotes glycolysis can be simply classified into three aspects: Promoting glucose uptake by cells, inhibiting the tricarboxylic acid (TCA) cycle and regulating the activity of glycolysis-related enzymes. The following are the signaling pathways regulated by HIF-1α found in the field of glycolytic metabolism in recent years.

ncRNAs alterations as initiating factors of HIF-1α/glycolysis axis

ncRNAs play an important regulatory role in HIF-1α-mediated glucose metabolism. Among them, miRNA, circRNA and lncRNA are common molecules involved in the regulation (Fig. 2). miR-182 promotes the mRNA expression of glycolysis-related enzymes alpha-enolase, glucose transporter 1 (GLUT1), hexokinase (HK) 1, HK2, lactate dehydrogenase (LDHA) and pyruvate dehydrogenase kinase-1 (PDK1) by upregulating HIF-1α (36). In addition, miRNA-31-5p overexpressed in NSCLC targets HIF-1α inhibitors to increase the activity of HIF-1α and then increase the expression of GLUT1, GAPDH, and LDHA to promote glycolysis (37). Meanwhile, miRNA-199a is downregulated in NSCLC, which reduces its target inhibitory effect on HIF-1α, causing the increased expression of HIF-1α. This further increases the expression of PDK1 to inhibit the TCA cycle (38).

In addition to the regulatory effect of changes in the expression of miRNAs themselves, some circRNAs can indirectly regulate the HIF-1α/glycolysis axis by regulating the expression of miRNAs. Among the upregulated circRNAs, circSLC25A16 and circAGFG1 promote glycolysis via miR-488-3p/HIF-1α/LDHA (39) and miR-28-5p/HIF-1α/GLUT1, phosphoglycerate kinase 1 and Pyruvate kinase M2 (PKM2) (40), respectively. Exosomal circSHKBP1 promotes the expression of PKM2 by inhibiting miR-1294 (41). PKM2 can not only accelerate glycolysis as a key enzyme but also promote the expression of HIF-1α-dependent glycolytic enzymes by activating HIF-1α (42). In addition, the expression of circLARP4 reduces the activity of HK2 and reduces the amount of glucose uptake and lactate excretion by cells. Downregulation of circLARP4 affects the miR-135b/PTEN/AKT/HIF-1α axis to promote glycolysis in NSCLC (43).

Furthermore, lncRNA-AC020978 is upregulated during hypoxia, increasing the stability of PKM2 by directly interacting with PKM2 to participate in the regulation of PKM2-enhanced HIF-1α transcription activity (44). lncRNA FAM83A-AS1 promotes glycolysis by inhibiting the ubiquitination of HIF-1α, which accumulates in cells and then promotes the expression of HK2 and LDHA (45).

Protein molecules alterations as initiating factors of HIF-1α/glycolysis axis

Several protein molecules are involved in specific HIF-1α-dependent regulation of glycolysis in NSCLC (Fig. 3). Part of the mechanism is centered on the altered expression of HK2 as the core of regulation. Echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) is a fusion protein found in 3–7% of NSCLC. EML4-ALK induces hypoxia-independent but glucose-dependent accumulation of HIF-1α via both transcriptional activation of HIF-1α mRNA and the PI3K-AKT pathway to enhance HIF-1α synthesis. In addition, the high expression of EML4-ALK promotes the binding of HIF-1α to HK2 promoter, which increases the expression of HK2 to promote glycolysis (46). Tumor necrosis factor receptor-associated factor 6 (TRAF6) is achieved by direct activation of AKT, which also causes the upregulation of HIF-1α/HK2 and promotes glycolysis (47).

Another key enzyme is PKM2. ERK in the MAPK signaling pathway promotes the endonuclear translocation of low-activity PKM2 and activates the Wnt pathway to promote the induced expression of HIF-1α by c-MYC and STAT3, thereby increasing the expression of multiple glycolytic related enzymes [phosphofructokinase (PFK1), PKM2, pyruvate dehydrogenase kinase 1 (PDK1) and LDHA] (48). Moreover, TEA domain 4 (TEAD4) can act as a transcription factor to promote the transcription of PKM2, which accelerates glycolysis and increases the activity of HIF-1α to increase the expression of GLUT1 and HK2 (49).

Finally, there are mechanisms associated with mTOR, which is the classical molecule that regulates HIF-1α translation. Under the condition of hypoxia in NSCLC, the expression of KLF transcription factor 5 (KLF5) increases to activate the PI3K/AKT/mTOR/HIF-1α pathway, increasing the glucose consumption and lactate production of tumor cells (50). Inflammatory interferon, such as IL-6, promotes the expression of glycolytic related genes by stimulating PI3k/AKT/mTOR to activate HIF-1α (51). At the same time, phosphorylated AMPKa1 can also stimulate mTOR/HIF-1α to increase the expression of GLUT1 and LDHA to promote glycolysis. Microtubule affinity regulating kinase 2/4 is highly expressed in advanced NSCLC to maintain the phosphorylation level of AMPKa1 and promote tumor cells to glycolysis (52).

The aforementioned studies show that most molecules typically act on HIF-1α ubiquitination and PI3K/AKT/mTOR signaling pathways that alter intracellular HIF-1α content and HIF-1α activity. At the same time, more ncRNAs and protein molecules upstream of HIF-1α in NSCLC tend to regulate HK2, LDHA and PKM2 to alter glycolytic processes. It is evident that blocking HIF-1α for the decreasing of HK2, PKM2 and LDHA transcription has the potential approach to achieve improved therapeutic effects.

Progress in targeting the HIF-1α/glycolysis axis for NSCLC treatment

Recent discoveries have elucidated mechanisms by which stable HIF-1α expression in hypoxic environments contributes to drug resistance and treatment ineffectiveness in NSCLC. Novel therapeutic strategies have emerged, focusing on targeting the HIF-1α-mediated hypoxic metabolic characteristics (Table I).

Table I.

Mechanisms of chemotherapy resistance and radiotherapy tolerance associated with HIF-1a/glycolysis.

Table I.

Mechanisms of chemotherapy resistance and radiotherapy tolerance associated with HIF-1a/glycolysis.

Author(s), yearTreatment modeResult or achievementMechanism(Refs.)
Gong et al, 2018ChemotherapyResistance to cisplatinKLF5 → PI3K/AKT/mTOR→ HIF-1a/glycolysis → resistance(50)
Sun et al, 2021 miRNA-21 → PI3K/AKT/mTOR pathway → HIF-1a/glycolysis → resistance(54)
Xu et al, 2020 circAKT3 → miR-516b-5p/STAT3 → resistance (inhibition of HIF-1a/glycolysis can attenuate this effect)(55)
Dong et al, 2020 Resistance to etoposideEtoposide→ ROS → HIF-1a/glycolysis → Lactic acid → TGF-β1/Snail and TAZ/AP-1 pathway → MRP1/ABCC1 proteins → resistance(56)
Sun et al, 2017 Resistance to paclitaxelGlucose uptake in paclitaxel resistant tumor cells is more dependent on the promotion of GLUT1 expression by PDK2 activated c-Myc and HIF-1a(57)
Grosso et al, 2013RadiotherapyLow sensitivity to radiotherapymiR-210 → HIF-1a/glycolysis → low sensitivity(59)
Zhang et al, 2019 Enhance sensitivityCyclocarya paliurus polysaccharide inhibits mTOR/AKT/PI3K pathway →HIF-1a↓ → apoptosis of hypoxic cells → sensitivity enhanced(60)
You et al, 2022TKIResistance to erlotinibSIRT6 → HIF-1a/HK2 → resistance(62)
Zhang et al, 2021New methods to treat tumor through metabolic pathway (Reduce the energy source of tumor cells)Hyperbaric oxygen therapyInhibit HIF-1a/PFKP axis(67)
Kim et al, 2015 PA-12PA-12 → Inhibit nuclear translocation of PKM2 → HIF-1a/glycolysis→(68)
Zhao et al, 2014 YC-1YC-1 → HIF-1↓→ The activity of LDHA and pyruvate dehydrogenase was downregulated → glycolysis→(69)
Zhou et al, 2017. AlbendazoleAlbendazole → HIF-1a↓ → glycolysis→(70)
Yang et al, 2021 Deoxypodophyllotoxin Deoxypodophyllotoxin→ parkin mediated protein degradation→ HIF-1a↓ → GLUT1/HK2/LDHA→(71)
Liu et al, 2021 HuaierHuaier→ inhibit PI3K/AKT/HIF-1a signaling pathway → glycolysis/glucose uptake↓(72)
Huang et al, 2022 NanoparticleDeliver EGFR-TKI and YAP-siRNA → HIF-1a↓ → Glycolysis↓(75)
Alkhathami et al, 2023 Deliver circRNA→ HIF-1a↓→Glycolysis↓(76)
Kopecka et al, 2015 Deliver Zoledronic acid→ inhibit Ras/erk1/2→ activation of HIF-1a ↓→glycolysis↓(53)

[i] HIF-1α, hypoxia-inducible factor 1α; PFKP, phosphofructokinase, platelet; KLF5, KLF transcription factor 5; miR, microRNA; circRNA, circular RNA; ROS, reactive oxygen species; GLUT1, glucose transporter 1; PDK1, pyruvate dehydrogenase kinase 1; LDHA, lactate dehydrogenase; PKM2, pyruvate kinase 2; PDH, pyruvate dehydrogenase.

Therapeutic desensitization

Chemotherapy is one of the major ways to treat tumors, but inherent or acquired chemo-resistance limits its clinical application. Platinum-based drugs, central to NSCLC chemotherapy, face resistance mechanisms that are multifaceted, including factors such as platinum transporters, detoxification systems and DNA repair processes (53). These resistance mechanisms are intricately linked to glucose metabolism regulation. It was found that knocking down KLF5 in NSCLC cells alleviated resistance to cisplatin (50). This process is closely linked to the promotion of HIF-1α-dependent glycolysis following deregulation of the KLF5/PI3K/AKT/mTOR pathway activation (50). miR-21 activates the PI3K/AKT/mTOR/HIF-1α pathway, leading to the upregulation of PKM2 and LDHA2 expression. These enzymes are glycolysis-related and are notably abundant in cisplatin-resistant NSCLC cells. Their heightened presence enhances glucose metabolism in tumor cells, contributing to their resistance against cisplatin. Consequently, the elevated expression of miR-21 emerges as a pivotal factor in the development of cisplatin resistance in NSCLC (54). circAKT3 is also a non-coding RNA that is highly expressed in cisplatin-resistant NSCLC. It diminishes the sensitivity of tumor tissue to cisplatin through the regulation of miR-516b-5p/STAT3. However, this effect can be alleviated by suppressing HIF-1α-mediated glycolysis (55). The utilization of etoposide in NSCLC treatment induces elevated intracellular ROS production. This effect activates HIF-1α-mediated metabolic reprogramming, resulting in an upsurge in glycolysis and subsequently leading to increased lactate production. Lactate can regulate the TGF-β1/Snail and TAZ/AP-1 pathways to activate the expression of MRP1/ABCC1 proteins that increase etoposide resistance (56). Scholars have also found that the resistance of NSCLC to paclitaxel is related to the glycolysis promoted by HIF-1α. Evidence suggests that in paclitaxel-resistant tumor cells, glucose uptake relies more on the promotion of GLUT1 expression by pyruvate dehydrogenase kinase 2-activated c-Myc and HIF-1α (57). The increase of HIF-1α-induced glycolysis always promotes the occurrence of drug resistance, which is in line with the current general hypothesis that inhibiting glycolysis can improve chemotherapy (58). However, studies on the relationship between HIF-1α-induced glycolysis and NSCLC resistance to chemotherapeutic agents are fragmented. Further exploration is needed to systematically refine the specific mechanisms involved.

Reduced sensitivity has also been seen in NSCLC radiotherapy. Alternative methods exist to reduce tumor responsiveness to radiation. Particularly, the regulation of the HIF-1α/glycolysis axis has been identified as a promising approach. Researchers have indicated that the stable expression of HIF-1 in NSCLC, achieved through the high expression of miR-210, further prompts cells to manifest mitochondrial defects and glycolytic phenotypes. The existence of this metabolic state is crucial for miR-210 to repair gene double-strand breaks in radiation-resistant NSCLC (59). Cyclocarya paliurus polysaccharide is mainly used to regulate blood glucose and has potential radiosensitization effects when combined with radiotherapy. The specific mechanism is that cyclocarya paliurus polysaccharide inhibits mTOR/AKT/PI3K pathway and reduces HIF-1α expression, which leads to apoptosis of hypoxic NSCLC cells (60). In conclusion, blocking HIF-1α-mediated Warburg effect can effectively enhance the sensitivity of hypoxic tumor tissue to radiotherapy.

EGFR mutants often appear in NSCLC, making EGFR tyrosine kinase inhibitor (TKI)-targeted therapy a prevalent treatment option, though it often encounters resistance issues. In normal cells, SIRT6 acts as a histone H3K9 deacetylase to control the expression of multiple glycolytic genes (61). However, in erlotinib-resistant NSCLC cells, elevated SIRT6 levels enhance glycolysis via the HIF-1α/HK2 axis, reducing the sensitivity of cells to erlotinib. HIF-1α blocker PX478-2HCL blocks this process to alleviate NSCLC resistance to erlotinib (62). Currently, few studies have explored the relationship between the mechanism of EGFR-TKI resistance and the HIF-1α/glycolytic axis. This scarcity might stem from variations in the understanding of tumor metabolic characteristics and their correlation with EGFR-TKI resistance across different academic findings. Some consider that glycolysis promotes EGFR-TKI resistance, while others consider that the metabolic characteristics of drug-resistant tissues tend to be oxidative phosphorylation (6366).

New treatment options

In recent years, several new NSCLC therapies targeting HIF-1α/glycolysis axis have been discovered (Table I). In hypoxic NSCLC cells, hyperbaric oxygen therapy disrupts the HIF-1α/phosphofructokinase, platelet axis, thus impeding the Warburg effect. This reduction in glycolytic capacity due to the high oxygen concentration effectively inhibits excessive tumor cell proliferation (67). PA-12, an activator of PKM2, can inhibit the nuclear translocation of PKM2 to suppress the expression of HIF-1. Therefore, the glycolysis promoted by HIF-1 is blocked, which affects the proliferation of tumor cells with limited energy supply during hypoxia (68). The HIF-1 inhibitor YC-1 targets the transient activation of LDHA and phosphorylation of the E1a subunit of pyruvate dehydrogenase, effectively inhibiting the metabolic shift from oxidative phosphorylation to glycolysis in tumors. This process impedes the metastatic potential of lung cancer (69). Albendazole is primarily employed as an anthelmintic and insect repellent (70). However, recent research has revealed its additional potential. Albendazole has been shown to downregulate the expression of HIF-1α and decrease the levels of HK, PK and LDH in tumor cells under hypoxic conditions. This mechanism inhibits glycolysis in NSCLC, ultimately impeding their proliferation (70). Deoxypodophyllotoxin hinders NSCLC progression through a two-fold mechanism. Initially, it disrupts angiogenesis in the tumor vicinity. Second, it facilitates parkin-mediated protein degradation, resulting in decreased expression of HIF-1α and subsequently reducing the levels of HIF-1α target genes such as GLUT1, HK2, and LDHA (71). The Chinese medicine Huaier is currently an adjunct drug in the treatment of a number of cancers. It can inactivate PI3K/AKT/HIF-1α pathway, downregulate glycolysis and glucose transport in NSCLC and exert anti-tumor effects (72). For squamous NSCLC, Fibroblast Growth Factor Receptor 1 (FGFR1) is often overexpressed. Targeting FGFR1 may prevent cancer cell growth by inhibiting glucose metabolism, as FGFR1 activates the AKT/mTOR pathway for HIF-1α accumulation and thus increases glucose uptake and glycolysis (73).

In addition, nanoparticles are gaining traction in tumor medicine, with ongoing clinical translation efforts (74). A newly invented nanodrug can simultaneously target the delivery of EGFR-TKI and yes associated protein (YAP)-siRNA combination drugs, addressing the role of YAP in epidermal growth factor receptor-TKI resistance in NSCLC. This nanodrug diminishes the glycolysis function by downregulating HIF-1α, enhancing tumor cell sensitivity to photodynamic therapy-induced apoptosis (75). Nanoparticles can be utilized to deliver circRNAs for the treatment of NSCLC. These circRNAs, either directly or through the inhibition of glycolysis via HIF-1α, hold promise as a therapeutic approach for NSCLC (76). Zoledronic acid-loaded nanoparticles suppress isoprenoid synthesis and HIF-1α activation through the Ras/erk1/2 pathway, decreasing glucose transport and glycolytic enzyme transcriptional activity. This method shows promise in combating multidrug-resistant tumors (53).

Conclusions

HIF is an important metabolic regulatory molecule in tumors and the dysregulation of HIF expression is necessary for tumor survival and growth (77). The expression of HIF-1α mainly affects the balance between glycolysis and oxidized phosphoric acid in higher metazoan tumor cells. However, there is no universal mechanism for reprogramming glucose metabolism in all cancers (58), so the present review focused on NSCLC. The present review summarized the regulatory mechanism of HIF-1α/glycolysis in order to discover the regulatory characteristics of glucose metabolism in NSCLC and paved the way for finding the mechanism that is common in different cancers. It characterized the regulatory mechanisms of HIF-1α in NSCLC according to different stages affecting HIF-1α expression, reflecting the unique regulatory pattern of HIF-1α in NSCLC. Part of the mechanism can be reflected in the mechanism of the regulation of HIF-1α-mediated glycolysis. For example, the inflammatory factor IL-6 can increase the expression of HIF-1α through STAT3 and promote glycolysis (29). The section ‘Regulatory mechanism of HIF-1α/glycolysis axis in NSCLC’ summarized the types of regulatory molecules and classical pathways as clues. It was found that ncRNA and PI3K/AKT/mTOR signaling pathways play an important role in regulating the HIF-1α/glycolysis axis, and most of them regulate the glycolysis process by affecting the downstream HK2 content. In addition, it was found that the accumulation of HIF-1α and the overexpression of HIF-1α promote glycolysis to form a cycle promoting a mutually stable relationship. Taking the regulatory mechanism in NSCLC as an example, HIF-1α can promote the expression of PKM2 to accelerate glycolysis. At the same time, low PKM2 activity leads to decreased glycolysis but can induce HIF-1α expression to solve this conundrum.

The mechanism of glucose metabolism reprogramming is gradually being analyzed, and it is generally considered that the regulation of glucose metabolism may be one of the important development directions for cancer treatment in the future (78). A variety of NSCLC treatment modalities and resistance mechanisms related to the HIF-1α/glycolysis axis were summarized in part three of the present review. The central idea behind these approaches is to alter the specific metabolic pattern of tumors by blocking HIF-1α expression and activation or disabling glycolytic rate-limiting enzyme to aid classical NSCLC therapy. However, in the case of tumor development led by HIF-1α/glycolysis, a more ideal therapeutic target is that of selective intervention of HIF-1 pathway (79). Selectivity can be manifested in the development of inhibitors that target molecules that regulate HIF-1α to initiate the transcription process of glycolytic enzymes, rather than HIF-1α or glycolytic rate-limiting enzymes or upstream molecules that regulate HIF-1α themselves. This allows for more precise regulation of HIF-1α-mediated changes in tumor metabolism without affecting other roles of HIF-1α and other molecules in complex signaling pathway networks. There are few relevant studies on HIF-1α initiating the transcription of glycolysis-related genes in NSCLC (46). If more targets that selectively inhibit this axis can be found in the future, it will promote the research of methods to treat NSCLC by regulating metabolism.

Acknowledgements

Not applicable.

Funding

The present study was supported by the National Training Program of Undergraduate Innovation and Entrepreneurship (grant no. 2022G19 to YS); Special Funds for the Cultivation of Guangdong College Students Scientific and Technological Innovation (grant no. Pdjh2022c0098 to XL); Shenzhen Municipal Science and Technology Innovation Commission Foundation (grant no. JCYJ20210324104800001 and JCYJ20220530114415036 to GC).

Availability of data and materials

Not applicable.

Authors' contributions

YS and GC conceived and designed the article. YS and XL surveyed the literature and wrote the manuscript. JW, ZZ and SC surveyed the literature and provided suggestions. All authors read and approved the final version of the manuscript. Data authentication is not applicable.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References

1 

Siegel RL, Miller KD, Wagle NS and Jemal A: Cancer statistics, 2023. CA Cancer J Clin. 73:17–48. 2023. View Article : Google Scholar : PubMed/NCBI

2 

General Office of National Health Commission of the People's Republic of China, . Primary lung cancer diagnosis and treatment guidelines (2022 edition). Med J Peking Union Med Coll Hosp. 13:549–570. 2022.

3 

Molina JR, Yang P, Cassivi SD, Schild SE and Adjei AA: Non-small cell lung cancer: Epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 83:584–594. 2008. View Article : Google Scholar : PubMed/NCBI

4 

Zahra K, Dey T, Ashis H, Mishra SP and Pandey U: Pyruvate Kinase M2 and Cancer: The Role of PKM2 in promoting tumorigenesis. Front Oncol. 10:1592020. View Article : Google Scholar : PubMed/NCBI

5 

Emami Nejad A, Najafgholian S, Rostami A, Sistani A, Shojaeifar S, Esparvarinha M, Nedaeinia R, Haghjooy Javanmard S, Taherian M, Ahmadlou M, et al: The role of hypoxia in the tumor microenvironment and development of cancer stem cell: A novel approach to developing treatment. Cancer Cell Int. 21:622021. View Article : Google Scholar : PubMed/NCBI

6 

Courtnay R, Ngo DC, Malik N, Ververis K, Tortorella SM and Karagiannis TC: Cancer metabolism and the Warburg effect: The role of HIF-1 and PI3K. Mol Biol Rep. 42:841–851. 2015. View Article : Google Scholar : PubMed/NCBI

7 

Wang GL and Semenza GL: General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proc Natl Acad Sci USA. 90:4304–4308. 1993. View Article : Google Scholar : PubMed/NCBI

8 

McGettrick AF and O'Neill LAJ: The role of HIF in immunity and inflammation. Cell Metab. 32:524–536. 2020. View Article : Google Scholar : PubMed/NCBI

9 

Semenza GL, Agani F, Booth G, Forsythe J, Iyer N, Jiang BH, Leung S, Roe R, Wiener C and Yu A: Structural and functional analysis of hypoxia-inducible factor 1. Kidney Int. 51:553–555. 1997. View Article : Google Scholar : PubMed/NCBI

10 

Kierans SJ and Taylor CT: Regulation of glycolysis by the hypoxia-inducible factor (HIF): Implications for cellular physiology. J Physiol. 599:23–37. 2021. View Article : Google Scholar : PubMed/NCBI

11 

Albadari N, Deng S and Li W: The transcriptional factors HIF-1 and HIF-2 and their novel inhibitors in cancer therapy. Expert Opin Drug Discov. 14:667–682. 2019. View Article : Google Scholar : PubMed/NCBI

12 

Palazón A, Aragonés J, Morales-Kastresana A, de Landázuri MO and Melero I: Molecular pathways: Hypoxia response in immune cells fighting or promoting cancer. Clin Cancer Res. 18:1207–1213. 2012. View Article : Google Scholar : PubMed/NCBI

13 

Taylor CT and Scholz CC: The effect of HIF on metabolism and immunity. Nat Rev Nephrol. 18:573–587. 2022. View Article : Google Scholar : PubMed/NCBI

14 

Kaelin WG: The von Hippel-Lindau tumor suppressor protein: Roles in cancer and oxygen sensing. Cold Spring Harb Symp Quant Biol. 70:159–166. 2005. View Article : Google Scholar : PubMed/NCBI

15 

Hampton-Smith RJ, Davenport BA, Nagarajan Y and Peet DJ: The conservation and functionality of the oxygen-sensing enzyme Factor Inhibiting HIF (FIH) in non-vertebrates. PLoS One. 14:e02161342019. View Article : Google Scholar : PubMed/NCBI

16 

Nguyen TL and Durán RV: Prolyl hydroxylase domain enzymes and their role in cell signaling and cancer metabolism. Int J Biochem Cell Biol. 80:71–80. 2016. View Article : Google Scholar : PubMed/NCBI

17 

Wang Q, Hu DF, Rui Y, Jiang AB, Liu ZL and Huang LN: Prognosis value of HIF-1α expression in patients with non-small cell lung cancer. Gene. 541:69–74. 2014. View Article : Google Scholar : PubMed/NCBI

18 

Yin X, Xia J, Sun Y and Zhang Z: CHCHD2 is a potential prognostic factor for NSCLC and is associated with HIF-1α expression. BMC Pulm Med. 20:402020. View Article : Google Scholar : PubMed/NCBI

19 

Fu R, Du W, Ding Z, Wang Y, Li Y, Zhu J, Zeng Y, Zheng Y, Liu Z and Huang JA: HIF-1α promoted vasculogenic mimicry formation in lung adenocarcinoma through NRP1 upregulation in the hypoxic tumor microenvironment. Cell Death Dis. 12:3942021. View Article : Google Scholar : PubMed/NCBI

20 

Li Y and Zhang Y, Li X, Huang Y, Chen W, He L and Zhang Y: Status of hypoxia-inducible factor-1α expression in non-small cell lung cancer. Pharmazie. 76:404–411. 2021.PubMed/NCBI

21 

Qi Q, Wang C, Yang J, Tian Y and Feng C: Correlation between HIF-1α, PD-L1 and lymphatic metastasis in non-small cell lung cancer. Chin J Lung Dis (Electronic Edition). 13:242–246. 2020.

22 

Yang SL, Ren QG, Wen L and Hu JL: Clinicopathological and prognostic significance of hypoxia-inducible factor-1 alpha in lung cancer: A systematic review with meta-analysis. J Huazhong Univ Sci Technol Med Sci. 36:321–327. 2016. View Article : Google Scholar

23 

Koren A, Rijavec M, Krumpestar T, Kern I, Sadikov A, Čufer T and Korošec P: Gene expression levels of the prolyl hydroxylase domain proteins PHD1 and PHD2 but not PHD3 are decreased in primary tumours and correlate with poor prognosis of patients with surgically resected Non-Small-Cell lung cancer. Cancers (Basel). 13:23092021. View Article : Google Scholar : PubMed/NCBI

24 

Chang YC, Chan YC, Chang WM, Lin YF, Yang CJ, Su CY, Huang MS, Wu ATH and Hsiao M: Feedback regulation of ALDOA activates the HIF-1α/MMP9 axis to promote lung cancer progression. Cancer Lett. 403:28–36. 2017. View Article : Google Scholar : PubMed/NCBI

25 

Kietzmann T and Görlach A: Reactive oxygen species in the control of hypoxia-inducible factor-mediated gene expression. Semin Cell Dev Biol. 16:474–486. 2005. View Article : Google Scholar : PubMed/NCBI

26 

Li J, Tuo Z, Zong Y and Liu J: Succinate dehydrogenase 5 regulates lung cancer metastasis by reprogramming glucose metabolism. J Thorac Dis. 13:6427–6438. 2021. View Article : Google Scholar : PubMed/NCBI

27 

Li Q, Huang Q, Cheng S, Wu S, Sang H and Hou J: Circ_ZNF124 promotes non-small cell lung cancer progression by abolishing miR-337-3p mediated downregulation of JAK2/STAT3 signaling pathway. Cancer Cell Int. 19:2912019. View Article : Google Scholar : PubMed/NCBI

28 

Wang M, Wang W, Ding J, Wang J and Zhang J: Downregulation of Rab17 promotes cell proliferation and invasion in non-small cell lung cancer through STAT3/HIF-1α/VEGF signaling. Thorac Cancer. 11:379–388. 2020. View Article : Google Scholar : PubMed/NCBI

29 

Fan H, Li J, Wang J and Hu Z: Long Non-Coding RNAs (lncRNAs) Tumor-Suppressive Role of lncRNA on Chromosome 8p12 (TSLNC8) inhibits tumor metastasis and promotes apoptosis by regulating interleukin 6 (IL-6)/Signal transducer and activator of transcription 3 (STAT3)/Hypoxia-Inducible factor 1-alpha (HIF-1α) signaling pathway in Non-Small cell lung cancer. Med Sci Monit. 25:7624–7633. 2019. View Article : Google Scholar : PubMed/NCBI

30 

Glück AA, Orlando E, Leiser D, Poliaková M, Nisa L, Quintin A, Gavini J, Stroka DM, Berezowska S, Bubendorf L, et al: Identification of a MET-eIF4G1 translational regulation axis that controls HIF-1α levels under hypoxia. Oncogene. 37:4181–4196. 2018. View Article : Google Scholar : PubMed/NCBI

31 

Qi L, Zhu F, Li SH, Si LB, Hu LK and Tian H: Retinoblastoma binding protein 2 (RBP2) promotes HIF-1α-VEGF-induced angiogenesis of non-small cell lung cancer via the Akt pathway. PLoS One. 9:e1060322014. View Article : Google Scholar : PubMed/NCBI

32 

Yang D, Liu J, Qian H and Zhuang Q: Cancer-associated fibroblasts: From basic science to anticancer therapy. Exp Mol Med. 55:1322–1332. 2023. View Article : Google Scholar : PubMed/NCBI

33 

Zhang J, Han L, Yu J, Li H and Li Q: miR-224 aggravates cancer-associated fibroblast-induced progression of non-small cell lung cancer by modulating a positive loop of the SIRT3/AMPK/mTOR/HIF-1α axis. Aging (Albany NY). 13:10431–10449. 2021. View Article : Google Scholar : PubMed/NCBI

34 

Liu XN, Zhang CB, Lin H, Tang XY, Zhou R, Wen HL and Li J: microRNA-204 shuttled by mesenchymal stem cell-derived exosomes inhibits the migration and invasion of non-small-cell lung cancer cells via the KLF7/AKT/HIF-1α axis. Neoplasma. 68:719–731. 2021. View Article : Google Scholar : PubMed/NCBI

35 

Chu X, Wang Z, Wang W, Liu W, Cao Y and Feng L: Roles of hypoxic environment and M2 macrophage-derived extracellular vesicles on the progression of non-small cell lung cancer. BMC Pulm Med. 23:2392023. View Article : Google Scholar : PubMed/NCBI

36 

Wang M, Wang W, Wang J and Zhang J: MiR-182 promotes glucose metabolism by upregulating hypoxia-inducible factor 1α in NSCLC cells. Biochem Biophys Res Commun. 504:400–405. 2018. View Article : Google Scholar : PubMed/NCBI

37 

Zhu B, Cao X, Zhang W, Pan G, Yi Q, Zhong W and Yan D: MicroRNA-31-5p enhances the Warburg effect via targeting FIH. FASEB J. 33:545–556. 2019. View Article : Google Scholar : PubMed/NCBI

38 

Ding G, Huang G, Liu HD, Liang HX, Ni YF, Ding ZH, Ni GY and Hua HW: MiR-199a suppresses the hypoxia-induced proliferation of non-small cell lung cancer cells through targeting HIF1α. Mol Cell Biochem. 384:173–180. 2013. View Article : Google Scholar : PubMed/NCBI

39 

Shangguan H, Feng H, Lv D, Wang J, Tian T and Wang X: Circular RNA circSLC25A16 contributes to the glycolysis of non-small-cell lung cancer through epigenetic modification. Cell Death Dis. 11:4372020. View Article : Google Scholar : PubMed/NCBI

40 

Ma X, Wang C, Chen J, Wei D, Yu F and Sun J: circAGFG1 sponges miR-28-5p to promote non-small-cell lung cancer progression through modulating HIF-1α level. Open Med (Wars). 16:703–717. 2021. View Article : Google Scholar : PubMed/NCBI

41 

Chen W, Tang D, Lin J, Huang X, Lin S, Shen G and Dai Y: Exosomal circSHKBP1 participates in non-small cell lung cancer progression through PKM2-mediated glycolysis. Mol Ther Oncolytics. 24:470–485. 2022. View Article : Google Scholar : PubMed/NCBI

42 

Luo W, Hu H, Chang R, Zhong J, Knabel M, O'Meally R, Cole RN, Pandey A and Semenza GL: Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell. 145:732–744. 2011. View Article : Google Scholar : PubMed/NCBI

43 

Lu H, Guo Q, Mao G, Zhu J and Li F: CircLARP4 suppresses cell proliferation, invasion and glycolysis and promotes apoptosis in non-small cell lung cancer by targeting miR-135b. Onco Targets Ther. 13:3717–3728. 2020. View Article : Google Scholar : PubMed/NCBI

44 

Hua Q, Mi B, Xu F, Wen J, Zhao L, Liu J and Huang G: Hypoxia-induced lncRNA-AC020978 promotes proliferation and glycolytic metabolism of non-small cell lung cancer by regulating PKM2/HIF-1α axis. Theranostics. 10:4762–4778. 2020. View Article : Google Scholar : PubMed/NCBI

45 

Chen Z, Hu Z, Sui Q, Huang Y, Zhao M, Li M, Liang J, Lu T, Zhan C, Lin Z, et al: LncRNA FAM83A-AS1 facilitates tumor proliferation and the migration via the HIF-1α/glycolysis axis in lung adenocarcinoma. Int J Biol Sci. 18:522–535. 2022. View Article : Google Scholar : PubMed/NCBI

46 

Ma Y, Yu C, Mohamed EM, Shao H, Wang L, Sundaresan G, Zweit J, Idowu M and Fang X: A causal link from ALK to hexokinase II overexpression and hyperactive glycolysis in EML4-ALK-positive lung cancer. Oncogene. 35:6132–6142. 2016. View Article : Google Scholar : PubMed/NCBI

47 

Feng L, Feng S, Nie Z, Deng Y, Xuan Y, Chen X, Lu Y, Liang L and Chen Y: TRAF6 promoted tumor glycolysis in non-small-cell lung cancer by activating the Akt-HIFα Pathway. Biomed Res Int. 2021:34312452021. View Article : Google Scholar : PubMed/NCBI

48 

Icard P, Simula L, Fournel L, Leroy K, Lupo A, Damotte D, Charpentier MC, Durdux C, Loi M, Schussler O, et al: The strategic roles of four enzymes in the interconnection between metabolism and oncogene activation in non-small cell lung cancer: Therapeutic implications. Drug Resist Updat. 63:1008522022. View Article : Google Scholar : PubMed/NCBI

49 

Hu Y, Mu H and Deng Z: The transcription factor TEAD4 enhances lung adenocarcinoma progression through enhancing PKM2 mediated glycolysis. Cell Biol Int. 45:2063–2073. 2021. View Article : Google Scholar : PubMed/NCBI

50 

Gong T, Cui L, Wang H, Wang H and Han N: Knockdown of KLF5 suppresses hypoxia-induced resistance to cisplatin in NSCLC cells by regulating HIF-1α-dependent glycolysis through inactivation of the PI3K/Akt/mTOR pathway. J Transl Med. 16:1642018. View Article : Google Scholar : PubMed/NCBI

51 

Yeh YH, Hsiao HF, Yeh YC, Chen TW and Li TK: Inflammatory interferon activates HIF-1α-mediated epithelial-to-mesenchymal transition via PI3K/AKT/mTOR pathway. J Exp Clin Cancer Res. 37:702018. View Article : Google Scholar : PubMed/NCBI

52 

Natarajan SR, Ponnusamy L and Manoharan R: MARK2/4 promotes Warburg effect and cell growth in non-small cell lung carcinoma through the AMPKα1/mTOR/HIF-1α signaling pathway. Biochim Biophys Acta Mol Cell Res. 1869:1192422022. View Article : Google Scholar : PubMed/NCBI

53 

Kopecka J, Porto S, Lusa S, Gazzano E, Salzano G, Giordano A, Desiderio V, Ghigo D, Caraglia M, De Rosa G and Riganti C: Self-assembling nanoparticles encapsulating zoledronic acid revert multidrug resistance in cancer cells. Oncotarget. 6:31461–31478. 2015. View Article : Google Scholar : PubMed/NCBI

54 

Sun Y, Liu W, Zhao Q, Zhang R, Wang J, Pan P, Shang H, Liu C and Wang C: Downregulating the expression of miRNA-21 inhibits the glucose metabolism of A549/DDP cells and promotes cell death through the PI3K/AKT/mTOR/HIF-1α pathway. Front Oncol. 11:6535962021. View Article : Google Scholar : PubMed/NCBI

55 

Xu Y, Jiang T, Wu C and Zhang Y: CircAKT3 inhibits glycolysis balance in lung cancer cells by regulating miR-516b-5p/STAT3 to inhibit cisplatin sensitivity. Biotechnol Lett. 42:1123–1135. 2020. View Article : Google Scholar : PubMed/NCBI

56 

Dong Q, Zhou C, Ren H, Zhang Z, Cheng F, Xiong Z, Chen C, Yang J, Gao J, Zhang Y, et al: Lactate-induced MRP1 expression contributes to metabolism-based etoposide resistance in non-small cell lung cancer cells. Cell Commun Signal. 18:1672020. View Article : Google Scholar : PubMed/NCBI

57 

Sun H, Zhu A, Zhou X and Wang F: Suppression of pyruvate dehydrogenase kinase-2 re-sensitizes paclitaxel-resistant human lung cancer cells to paclitaxel. Oncotarget. 8:52642–52650. 2017. View Article : Google Scholar : PubMed/NCBI

58 

Chelakkot C, Chelakkot VS, Shin Y and Song K: Modulating glycolysis to improve cancer therapy. Int J Mol Sci. 24:26062023. View Article : Google Scholar : PubMed/NCBI

59 

Grosso S, Doyen J, Parks SK, Bertero T, Paye A, Cardinaud B, Gounon P, Lacas-Gervais S, Noël A, Pouysségur J, et al: MiR-210 promotes a hypoxic phenotype and increases radioresistance in human lung cancer cell lines. Cell Death Dis. 4:e5442013. View Article : Google Scholar : PubMed/NCBI

60 

Zhang F, Fan B and Mao L: Radiosensitizing effects of Cyclocarya paliurus polysaccharide on hypoxic A549 and H520 human non-small cell lung carcinoma cells. Int J Mol Med. 44:1233–1242. 2019.PubMed/NCBI

61 

Zhong L, D'Urso A, Toiber D, Sebastian C, Henry RE, Vadysirisack DD, Guimaraes A, Marinelli B, Wikstrom JD, Nir T, et al: The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha. Cell. 140:280–293. 2010. View Article : Google Scholar : PubMed/NCBI

62 

You Q, Wang J, Yu Y, Li F, Meng L, Chen M, Yang Q, Xu Z, Sun J, Zhuo W and Chen Z: The histone deacetylase SIRT6 promotes glycolysis through the HIF-1α/HK2 signaling axis and induces erlotinib resistance in non-small cell lung cancer. Apoptosis. 27:883–898. 2022. View Article : Google Scholar : PubMed/NCBI

63 

Wang J, Liu X, Huang Y, Li P, Yang M, Zeng S, Chen D, Wang Q, Liu H, Luo K and Deng J: Targeting nicotinamide N-methyltransferase overcomes resistance to EGFR-TKI in non-small cell lung cancer cells. Cell Death Discov. 8:1702022. View Article : Google Scholar : PubMed/NCBI

64 

Kim S, Im JH, Kim WK, Choi YJ, Lee JY, Kim SK, Kim SJ, Kwon SW and Kang KW: Enhanced sensitivity of nonsmall cell lung cancer with acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors to phenformin: The roles of a metabolic shift to oxidative phosphorylation and redox balance. Oxid Med Cell Longev. 2021:54283642021. View Article : Google Scholar : PubMed/NCBI

65 

Dyrstad SE, Lotsberg ML, Tan TZ, Pettersen IKN, Hjellbrekke S, Tusubira D, Engelsen AST, Daubon T, Mourier A, Thiery JP, et al: Blocking aerobic glycolysis by targeting pyruvate dehydrogenase kinase in combination with EGFR TKI and ionizing radiation increases therapeutic effect in non-small cell lung cancer cells. Cancers (Basel). 13:9412021. View Article : Google Scholar : PubMed/NCBI

66 

Cheng FJ, Chen CH, Tsai WC, Wang BW, Yu MC, Hsia TC, Wei YL, Hsiao YC, Hu DW, Ho CY, et al: Cigarette smoke-induced LKB1/AMPK pathway deficiency reduces EGFR TKI sensitivity in NSCLC. Oncogene. 40:1162–1175. 2021. View Article : Google Scholar : PubMed/NCBI

67 

Zhang L, Ke J, Min S, Wu N, Liu F, Qu Z, Li W, Wang H, Qian Z and V Wang X: Hyperbaric oxygen therapy represses the warburg effect and epithelial-mesenchymal transition in hypoxic NSCLC cells via the HIF-1α/PFKP Axis. Front Oncol. 11:6917622021. View Article : Google Scholar : PubMed/NCBI

68 

Kim DJ, Park YS, Kim ND, Min SH, You YM, Jung Y, Koo H, Noh H, Kim JA, Park KC and Yeom YI: A novel pyruvate kinase M2 activator compound that suppresses lung cancer cell viability under hypoxia. Mol Cells. 38:373–379. 2015. View Article : Google Scholar : PubMed/NCBI

69 

Zhao T, Zhu Y, Morinibu A, Kobayashi M, Shinomiya K, Itasaka S, Yoshimura M, Guo G, Hiraoka M and Harada H: HIF-1-mediated metabolic reprogramming reduces ROS levels and facilitates the metastatic colonization of cancers in lungs. Sci Rep. 4:37932014. View Article : Google Scholar : PubMed/NCBI

70 

Zhou F, Du J and Wang J: Albendazole inhibits HIF-1α-dependent glycolysis and VEGF expression in non-small cell lung cancer cells. Mol Cell Biochem. 428:171–178. 2017. View Article : Google Scholar : PubMed/NCBI

71 

Yang Y, Liu L, Sun J, Wang S, Yang Z, Li H, Huang N and Zhao W: Deoxypodophyllotoxin inhibits non-small cell lung cancer cell growth by reducing HIF-1α-Mediated glycolysis. Front Oncol. 11:6295432021. View Article : Google Scholar : PubMed/NCBI

72 

Liu X, Liu L, Chen K, Sun L, Li W and Zhang S: Huaier shows anti-cancer activities by inhibition of cell growth, migration and energy metabolism in lung cancer through PI3K/AKT/HIF-1α pathway. J Cell Mol Med. 25:2228–2237. 2021. View Article : Google Scholar : PubMed/NCBI

73 

Fumarola C, Cretella D, La Monica S, Bonelli MA, Alfieri R, Caffarra C, Quaini F, Madeddu D, Falco A, Cavazzoni A, et al: Enhancement of the anti-tumor activity of FGFR1 inhibition in squamous cell lung cancer by targeting downstream signaling involved in glucose metabolism. Oncotarget. 8:91841–91859. 2017. View Article : Google Scholar : PubMed/NCBI

74 

Sun L, Liu H, Ye Y, Lei Y, Islam R, Tan S, Tong R, Miao YB and Cai L: Smart nanoparticles for cancer therapy. Signal Transduct Target Ther. 8:4182023. View Article : Google Scholar : PubMed/NCBI

75 

Huang J, Zhuang C, Chen J, Chen X, Li X, Zhang T, Wang B, Feng Q, Zheng X, Gong M, et al: Targeted Drug/Gene/Photodynamic therapy via a stimuli-responsive dendritic-polymer-based nanococktail for treatment of EGFR-TKI-resistant Non-small-cell lung cancer. Adv Mater. 34:e22015162022. View Article : Google Scholar : PubMed/NCBI

76 

Alkhathami AG, Sahib AS, Al Fayi MS, Fadhil AA, Jawad MA, Shafik SA, Sultan SJ, Almulla AF and Shen M: Glycolysis in human cancers: Emphasis circRNA/glycolysis axis and nanoparticles in glycolysis regulation in cancer therapy. Environ Res. 234:1160072023. View Article : Google Scholar : PubMed/NCBI

77 

Martínez-Reyes I and Chandel NS: Cancer metabolism: Looking forward. Nat Rev Cancer. 21:669–680. 2021. View Article : Google Scholar : PubMed/NCBI

78 

Xiao Y, Yu TJ, Xu Y, Ding R, Wang YP, Jiang YZ and Shao ZM: Emerging therapies in cancer metabolism. Cell Metab. 35:1283–1303. 2023. View Article : Google Scholar : PubMed/NCBI

79 

Zheng F, Chen J, Zhang X, Wang Z, Chen J, Lin X, Huang H, Fu W, Liang J, Wu W, et al: The HIF-1α antisense long non-coding RNA drives a positive feedback loop of HIF-1α mediated transactivation and glycolysis. Nat Commun. 12:13412021. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

April-2024
Volume 51 Issue 4

Print ISSN: 1021-335X
Online ISSN:1791-2431

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Shi Y, Lin X, Wang J, Zhou Z, Chen S and Chen G: Advances of HIF‑1α/glycolysis axis in non‑small cell lung cancer (Review). Oncol Rep 51: 55, 2024.
APA
Shi, Y., Lin, X., Wang, J., Zhou, Z., Chen, S., & Chen, G. (2024). Advances of HIF‑1α/glycolysis axis in non‑small cell lung cancer (Review). Oncology Reports, 51, 55. https://doi.org/10.3892/or.2024.8714
MLA
Shi, Y., Lin, X., Wang, J., Zhou, Z., Chen, S., Chen, G."Advances of HIF‑1α/glycolysis axis in non‑small cell lung cancer (Review)". Oncology Reports 51.4 (2024): 55.
Chicago
Shi, Y., Lin, X., Wang, J., Zhou, Z., Chen, S., Chen, G."Advances of HIF‑1α/glycolysis axis in non‑small cell lung cancer (Review)". Oncology Reports 51, no. 4 (2024): 55. https://doi.org/10.3892/or.2024.8714