ENO1 deletion potentiates ferroptosis and decreases glycolysis in colorectal cancer cells via AKT/STAT3 signaling
- Authors:
- Published online on: February 5, 2024 https://doi.org/10.3892/etm.2024.12415
- Article Number: 127
-
Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Colorectal cancer (CRC) is a recognized form of gastrointestinal malignancy that encompasses colon and rectal cancer (1). Globally, an estimated 1.8 million new cases of CRC occur annually, the incidence rate and mortality rate of which respectively account for 10 and 9.4% of all cancers (2,3). The outcome of patients with CRC remains negative due to metastasis and recurrence in spite of the great advances that have been witnessed in the therapeutic modalities of CRC including surgery, chemotherapy, radiotherapy, immunotherapy and targeted therapy (4-6). Moreover, epidemiological studies have consistently displayed the obvious interaction between the risk of CRC and other human diseases, such as inflammatory bowel disease, obesity and diabetes (7,8). Therefore, the poorly understood molecular mechanism of CRC needs to be further elucidated and the potential key molecular drivers remain to be developed.
Enolase (ENO) is a key glycolytic enzyme that is responsible for the transformation of 2-phosphoglycerate into phosphoenolpyruvate (9). In addition to its role as a glycolytic enzyme, α-enolase (ENO1), the most extensively studied isoform of ENO, is expressed on the cell surface of most tumors and has been shown to be an oncogenic factor in multiple cancers that depends on the modulation of a variety of biological events, such as glycolysis, angiogenesis, invasion and metastasis (10,11). In particular, interference with ENO1 has been shown to decrease glycolysis, cell growth, metastasis and chemotherapy resistance in CRC (12-14).
Mounting evidence has demonstrated that multiple biological signaling cascades are involved in the occurrence and development of CRC (15,16). The PI3K/AKT and STAT3 pathways are both classical signaling pathways implicated in the diverse phenotypes of tumor cells (17,18). Notably, it is increasingly reported that AKT/STAT3 signaling is dysregulated and activation of JAK2/STAT3 signaling may contribute to the malignant progression of CRC (19,20). In addition, Sun et al (21) clarified that ENO1 may act as a modulator of AKT signaling to participate in the process of gastric cancer.
The present study endeavored to explore whether ENO1 functioned in CRC via mediating AKT/STAT3 signaling.
Materials and methods
Cell culture and treatment
Fetal bovine serum (10%; FBS; BeNa Culture Collection) was added to Dulbecco's Modified Eagle's Medium-high glucose (DMEM-H; BeNa Culture Collection), F-12K medium (BeNa Culture Collection), L-15 medium (BeNa Culture Collection) and Roswell Park Memorial Institute (RPMI)-1640 medium (BeNa Culture Collection) at 37˚C with 5% CO2 for the incubation of CRC cell lines (Caco2, LoVo, SW480 and HCT116) procured from BeNa Culture Collection, separately. Human intestinal epithelial cell line (HIEC-6) procured from Zhejiang Meisen Cell Technology Co., Ltd., was also cultured in DMEM-H with 10% FBS. In addition, HCT116 cells were stimulated by 80 µM WZB117 (Shanghai Topscience Co., Ltd.) for 24 h (22) or 5 µM SC79 (Shanghai Topscience Co., Ltd.) for 2 h (23).
Transfection of plasmids
Using Lipofectamine® 2000 (Invitrogen; Thermo Fisher Scientific, Inc.), the specific small interfering (si)RNAs for ENO1 (siRNA-ENO1-1/2) and the corresponding negative control (siRNA-NC) from Guangzhou Geneseed Biotech Co., Ltd., were transfected into HCT116 cells. Briefly, 2x105 cells were seeded in a 6-well plate. When the cell fusion efficiency was 30-50%, 2 ml of a pre-prepared transfection complex containing 50 nM siRNA was added to each well. The cells were cultured at 37˚C with 5% CO2 for 6 h and then the medium was changed to continue the culture. The cells were collected 48 h post-transfection for further experiments. The siRNA sequences used were as follows: siRNA-ENO1-1: 5'-GTGTCCCTTGCCGTCTGCAAAGC-3', siRNA-ENO1-2: 5'-ATCAATGGCGGTTCTCATGCTGG-3', siRNA-NC: 5'-TCGTTGGCACTTCGGGTCTGCTAG-3'.
Cell Counting Kit-8 (CCK-8)
Transfected HCT116 cells in 96-well plates were exposed to 80 µM WZB117 or 5 µM SC79 after the adjustment of cell density to 5x103 cells/well. Each well was cultivated for extra 2 h at 37˚C following addition of 10 µl CCK-8 solution (Selleck Chemicals). Cell activity was assessed by estimating OD450 nm value by a microplate reader (Huaan Magnech Bio-Tech Co., Ltd.).
5-Ethynyl-2'-deoxyuridine (EdU) staining
Cell proliferation was measured via the employment of iClick EdU Andy Fluor 488 Imaging Kit (Guangzhou FulenGen Co., Ltd.). In brief, the transfected HCT116 cells (1x104 cells/well) subjected to 96-well plates were exposed to WZB117 or SC79, prior to the addition of EdU (20 µM per well) for 2 h at 37˚C as per the manufacturer's instructions. Afterwards, cells were probed with iClick EdU reaction buffer and stained with Hoechst 33342 for 10 min at room temperature following 15 min of fixation with 3.7% paraformaldehyde and 20 min of permeabilization with 0.5% Triton X-100 at room temperature. Images were prepared for observation under a fluorescence microscope (Motic China Group Co., Ltd.).
Estimation of total iron level
Following centrifugation at 3,000 x g for 10 min at 4˚C, total iron level in the cell supernatants was examined with Iron test kit (cat. no. ST1020; Leagene; Beijing Regan Biotechnology Co., Ltd.). OD562 nm value was determined using a spectrophotometer (Shimadzu Corporation).
Evaluation of ferroptosis markers
Following the centrifugation of HCT116 cells at 10,000 x g for 10 min at 4˚C, glutathione (GSH) and malondialdehyde (MDA) levels were examined with GSH Assay Kit (cat. no. TO1036; Leagene; Beijing Regan Biotechnology Co., Ltd.) and MDA Assay Kit (cat. no. TO1011; Leagene; Beijing Regan Biotechnology Co., Ltd.). The absorbance value at 412 and 535 nm was read with a spectrophotometer (Shimadzu Corporation).
Detection of intracellular reactive oxygen species (ROS)
Intracellular ROS was estimated using a Reactive Oxygen Species Assay Kit (cat. no. BES-BK2782B; Shanghai Bolson Biotechnology Co., Ltd.). After indicated transfection and treatment, HCT116 cells plated into 24-well plate (3x103 cells/well) were treated with 10 µΜ dichlorodihydrofluorescein diacetate (DCFH-DA) at 37˚C for 20 min in the dark. The cells were then centrifuged at 1,000 x g for 5 min at 4˚C. Subsequently, the supernatant was removed and the cell pellet was resuspended in PBS. ROS production was determined under a fluorescence microscope at 480 nm excitation/590 nm emission.
Analysis of extracellular acidification rates (ECAR)
The Seahorse XF Glycolysis Stress Test Kit (Agilent Technologies, Inc.) was used for the ECAR assay. Briefly, 5x104 HCT116 cells were plated on 96-well cell culture XF microplates (Agilent Technologies, Inc.) for 24 h at 37˚C, which was then replaced by the medium without glucose and pyruvate. 10 mM glucose, 1 µM oligomycin and 100 mM 2-deoxy-glucose (2-DG) were sequentially added to the cell medium, with two measurements after each treatment. The results were subjected to analysis with Seahorse Bioscience XF96 Extracellular Flux Analyzer (Agilent Technologies, Inc.).
Detection of glucose consumption and lactate level
HCT116 cells inoculated in 96-well plates at a density of 2x106 cells/well at 37˚C received the indicated transfection and treatment. Using a L-Lactate Assay Kit (cat. no. ab65330; Abcam) and Glucose Colorimetric Assay Kit (cat. no. ab282922; Abcam), lactate production and glucose consumption were respectively determined and were normalized to total protein concentration quantified by the BCA method (Shanghai Rongsheng Biotech Co., Ltd.).
Western blotting
Following the homogenization of HCT116 cells in RIPA buffer (Fude Biological Technology, Co. Ltd.), the BCA method (Shanghai Rongsheng Biotech Co., Ltd.) was used to measure protein content. Subsequently, 12 µg of protein was fractionated on 12% SDS-PAGE and transferring onto the PVDF membranes. The membranes were then blocked with 5% BSA for 1 h at room temperature (Beijing Solarbio Science & Technology Co., Ltd.) and immunoblotted with primary antibodies including ENO1 (cat. no. ab227978; 1:1,000), glucose transporter type 1 (GLUT1; cat. no. ab115730; 1:100,000), hexokinase 2 (HK2; cat. no. ab209847; 1:1,000), pyruvate kinase M2 isoform (PKM2; cat. no. ab85555; 1:1,000), glutathione peroxidase 4 (GPX4; cat. no. ab125066; 1:1,000), ferritin heavy chain 1 (FTH1; cat. no. ab75972; 1:1,000), acyl-CoA synthetase long-chain family member 4 (ACSL4; cat. no. ab155282; 1:10,000), AKT (cat. no. ab179463; 1:10,000), phosphorylated (p-)AKT (cat. no. ab38449; 1:1,000), STAT3 (cat. no. ab109085; 1:10,000), p-STAT3 (cat. no. ab267373; 1:1,000) and β-actin (cat. no. ab213262; 1:1,000) from Abcam at 4˚C overnight, prior to being incubated with HRP-conjugated secondary antibody (ab6721; 1:2,000; Abcam) for 1.5 h at 37˚C. The visualization of the blots was performed by the Super ECL Plus from Biorigin (Beijing) Inc. and the densitometry was performed using ImageJ software (v. 1.4; National Institutes of Health).
Statistical analysis
Following analysis with GraphPad Prism 8 software (GraphPad Software; Dotmatics), all data were reported as mean ± standard error of mean. The unpaired student's t-test was used to compare the significance between two groups, and the one-way ANOVA and Tukey's post hoc test were used for multiple comparisons. P<0.05 was considered to indicate a statistically significant difference.
Results
ENO1 expression is raised in CRC cells
To identify the role of ENO1 in CRC, ENO1 expression in CRC cells was initially tested. Using western blotting, it was found that ENO1 displayed higher expression in CRC cell lines (Caco2, LoVo, SW480 and HCT116) in contrast to a human intestinal epithelial cell line (HIEC-6; Fig. 1A). Accordingly, HCT116 cells were used in the following experiments. To determine the effects of ENO1 on the biological processes of CRC, ENO1 expression was distinctly weakened after transfection of siRNA-ENO1-1/2 plasmids. SiRNA-ENO1-2 was chosen for the follow-up assays since ENO1 showed lower expression in SiRNA-ENO1-2 group compared with the SiRNA-ENO1-1 group (Fig. 1B).
Deletion of ENO1 impedes the glycolysis of CRC cells
As depicted in Fig. 2A, following ENO1 knockdown, the ECAR was markedly decreased in HCT116 cells. In addition, inhibition of ENO1 resulted in the downregulation of glucose consumption and lactate production (Fig. 2B and C). Western blot analysis revealed that the expression of glycolysis-related GLUT1, HK2 and PKM2 were all lowered when ENO1 was depleted (Fig. 2D). All these findings suggested that ENO1 downregulation produced protective properties on the glycolysis of CRC cells.
ENO1 deficiency hampers the proliferation of CRC cells
As reported, glycolysis can serve as a driver of tumor cell proliferation. To investigate whether ENO1 participated in CRC cell proliferation via mediating glycolysis, WZB117, a specific inhibitor of GLUT1, was used. The experimental data from CCK-8 assay showed that the cell viability was reduced in the WZB117 group compared with the control group, and further attenuated after the simultaneous use of WZB117 and siRNA-ENO1 (Fig. 3A). As expected, EdU staining results showed that the fluorescence intensity of WZB117 group was slightly decreased compared with the control group, while after the use of SiRNA-ENO1, the fluorescence intensity of WZB117+iRNA-ENO1 group was significantly decreased compared with the other three groups (Fig. 3B). In conclusion, the suppressive role of GLUT1 inhibitor in CRC cell proliferation was strengthened by knockdown of ENO1.
Absence of ENO1 intensifies the ferroptosis of CRC cells
Ferroptosis remains a pivotal event during the process of CRC (24). It was noted that ENO1 reduction evidently raised total iron and MDA levels but lessened GSH level (Fig. 4A and B). The results of DCFH-DA staining reflected that intracellular ROS level was noticeably elevated when ENO1 was downregulated (Fig. 4C). Western blotting also revealed that GPX4, FTH1 expressions were depleted and ACSL4 expression was augmented in ENO1-silenced HCT116 cells (Fig. 4D). Overall, ENO1 insufficiency might contribute to the ferroptosis of CRC cells.
Knockdown of ENO1 inactivates AKT/STAT3 signaling to decrease the glycolysis, proliferation and potentiate the ferroptosis of HCT116 cells
At the same time, the expressions of proteins involved in AKT/STAT3 signaling were examined and it proved that inhibition of ENO1 significantly depleted p-AKT/AKT and p-STAT3/STAT3 expressions, which were then both partially recovered by treatment with SC79, an activator of AKT (Fig. 5A), suggesting that ENO1 deletion blocked AKT/STAT3 signaling in CRC cells. Moreover, SC79 was further applied to show that ENO1 participated in the glycolysis and ferroptosis of CRC cells through mediating AKT/STAT3 signaling. SC79 was discovered to increase the ECAR which was on a downward trend in HCT116 cells transfected with SiRNA-ENO1 (Fig. 5B). In addition, the suppressed lactate production and glucose consumption caused by ENO1 interference were partially reversed by SC79 (Fig. 5C and D). GLUT1, HK2 and PKM2 expressions all fell in ENO1-silencing HCT116 cells, but were restored by SC79 (Fig. 5E). CCK-8 and EdU staining assays revealed that the attenuated proliferative capacity of HCT116 cells attributed to ENO1 insufficiency was improved by activation of AKT (Fig. 6A and B). Furthermore, the increasing total iron and MDA levels and the falling GSH level following knockdown of ENO1 in HCT116 cells were all reversed by SC79 (Fig. 7A and B). Similarly, absence of ENO1 accelerated the generation of intracellular ROS, which was halted by SC79 (Fig. 7C). ENO1 deletion also reduced GPX4 and FTH1 expressions while increasing ACSL4 expression, which were all nullified by SC79 (Fig. 7D). Activation of AKT/STAT3 signaling counteracted the effects of ENO1 deficiency on the glycolysis, proliferation and ferroptosis of CRC cells.
Discussion
CRC is a heterogeneous disease with different gene expression patterns and the identification of genetic molecular markers may be conducive to predict the prognosis of CRC and provide an alternative treatment option for CRC (25-27). ENO1 is a multifunctional protein that has been revealed to be aberrantly expressed in multiple human malignancies, such as breast cancer, gastric cancer, head and neck cancer, and to be related to the disease progression (10). Studies have also revealed that ENO1 expression is upregulated and expedites the tumorigenesis and metastasis in CRC (28,29). Consistent with these findings, ENO1 expression was notably elevated in CRC cells.
The oncogenesis and development of CRC is a multistep process. The dysregulation of metabolism is one of the most characteristic features of solid tumors and altered metabolic patterns are observed in various types of cancer cells (30). Specifically, cancer cells primarily absorb energy dependent on a metabolic phenotype known as aerobic glycolysis that is also recognized as a phenomenon termed the Warburg effect, where cancer cells preferentially convert glucose to lactate (31). It is widely accepted that aerobic glycolysis plays a critical role in promoting the tumorigenesis of CRC (32,33). As an essential enzyme in the process of glycolysis, ENO1 has been hypothesized to exert pivotal functions in aerobic glycolysis in a variety of tumors, such as lung adenocarcinoma (34), pancreatic cancer (35) and gastric cancer (36). Zhan et al (14) verified that ENO1 induces lactate production in CRC cells. The present study also showed that ENO1 silencing might counteract glycolysis in CRC, as evidenced by reduced lactate production, glucose consumption and decreased ECAR in HCT116 cells. HK2 and PKM2 are identified as rate-limiting enzymes catalyzing the first or the final step of glycolysis pathway, respectively (37). GLUT1 is also a key rate-limiting factor in the transport and metabolism of glucose in cancer cells (38). In addition, aerobic glycolysis has been reported to facilitate the proliferation of cancer cells (39). Meanwhile, ENO1 is considered to be a driver of CRC cell proliferation (14,29). As expected, in the present study, after ENO1 knockdown, GLUT1, HK2 and PKM2 expressions all declined. The GLUT1 inhibitor WZB117 was used in the current study and it was noted that the viability and proliferation of CRC cells were both diminished by WZB117, which was further exacerbated by interference with ENO1.
Ferroptosis is a morphologically and biochemically novel form of cell death distinct from necrosis, autophagy, and apoptosis, and it is predominantly dictated by iron overload, lipid peroxidation and excess ROS production (40,41). Ferroptosis has been implicated in the etiology of CRC and targeting ferroptosis is a promising treatment strategy for CRC (42). Moreover, a recent study mentioned that ENO1 is highly associated with ferroptosis in hepatocellular carcinoma cells (43). GSH catalyzed by GPX4 is an intracellular antioxidant defense to scavenge the toxic lipid ROS and MDA is a product of lipid peroxidation (44,45). FTH1 is a ferroptosis-inhibiting protein while ACSL4 is a ferroptosis-promoting protein (46). ENO1 depletion was found to play a stimulatory role in ferroptosis events which were manifested as depleted GSH, GPX4 and FTH1, elevated iron release, ROS production, MDA and ACSL4.
AKT, belonging to the serine/threonine kinase family, is a proto-oncogene that can mediate cancer cell ferroptosis and glycolysis (47,48). STAT3 is an important transcription factor that also participates in the ferroptosis and glycolysis of tumor cells (49,50). Furthermore, AKT serves as an upstream regulator of STAT3 and may activate STAT3(51). Concurrently, interference with ENO1 can reduce p-AKT expression in gastric cancer (21). In the present study, it was also observed that the lowered p-AKT/AKT and p-STAT3/STAT3 expressions in HCT116 cells caused by absence of ENO1 were then both partially enhanced by treatment with AKT activator SC79. Abundant evidence has demonstrated that the AKT/STAT3 signaling pathway plays a vital role in the ferroptosis and glycolysis in CRC (52-54). Furthermore, the present experimental results also validated that SC79 reversed the influences of ENO1 on the glycolysis, proliferation as well as ferroptosis of HCT116 cells.
Altogether, ENO1 might stimulate glycolysis and obstruct ferroptosis in CRC cells by regulating AKT/STAT3 signaling. This finding suggested ENO1 as a prospective target for CRC and implied that inhibition of ENO1 may provide and effective therapeutic strategy for CRC.
Acknowledgements
Not applicable.
Funding
Funding: Not applicable.
Availability of data and materials
The data generated in the present study may be requested from the corresponding author.
Authors' contributions
YL performed most of the experiments and wrote the manuscript. YL and FZ were involved in cell culture. YH assisted YL in performing western blot analyses and FZ assisted YL in conducting CCK-8, EdU and ROS experiments. YL and YH both participated in the statistical analysis. YH and XW designed and supervised the study. YL and XW confirm the authenticity of all the raw data. All authors have read and approved the final manuscript.
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
|
Yang Y, Meng WJ and Wang ZQ: MicroRNAs in colon and rectal cancer-novel biomarkers from diagnosis to therapy. Endocr Metab Immune Disord Drug Targets. 20:1211–2126. 2020.PubMed/NCBI View Article : Google Scholar | |
|
Siegel RL, Miller KD, Goding Sauer A, Fedewa SA, Butterly LF, Anderson JC, Cercek A, Smith RA and Jemal A: Colorectal cancer statistics, 2020. CA Cancer J Clin. 70:145–164. 2020.PubMed/NCBI View Article : Google Scholar | |
|
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 71:209–49. 2021.PubMed/NCBI View Article : Google Scholar | |
|
Johdi NA and Sukor NF: Colorectal cancer immunotherapy: options and strategies. Front Immunol. 11(1624)2020.PubMed/NCBI View Article : Google Scholar | |
|
Piawah S and Venook AP: Targeted therapy for colorectal cancer metastases: A review of current methods of molecularly targeted therapy and the use of tumor biomarkers in the treatment of metastatic colorectal cancer. Cancer. 125:4139–4147. 2019.PubMed/NCBI View Article : Google Scholar | |
|
De Rosa M, Pace U, Rega D, Costabile V, Duraturo F, Izzo P and Delrio P: Genetics, diagnosis and management of colorectal cancer (review). Oncol Rep. 34:1087–1096. 2015.PubMed/NCBI View Article : Google Scholar | |
|
Keller DS, Windsor A, Cohen R and Chand M: Colorectal cancer in inflammatory bowel disease: Review of the evidence. Tech Coloproctol. 23:3–13. 2019.PubMed/NCBI View Article : Google Scholar | |
|
Soltani G, Poursheikhani A, Yassi M, Hayatbakhsh A, Kerachian M and Kerachian MA: Obesity, diabetes and the risk of colorectal adenoma and cancer. BMC Endocr Disord. 19(113)2019.PubMed/NCBI View Article : Google Scholar | |
|
Ji H, Wang J, Guo J, Li Y, Lian S, Guo W, Yang H, Kong F, Zhen L, Guo L and Liu Y: Progress in the biological function of alpha-enolase. Anim Nutr. 2:12–17. 2016.PubMed/NCBI View Article : Google Scholar | |
|
Huang CK, Sun Y, Lv L and Ping Y: ENO1 and cancer. Mol Ther Oncolytics. 24:288–298. 2022.PubMed/NCBI View Article : Google Scholar | |
|
Qiao G, Wu A, Chen X, Tian Y and Lin X: Enolase 1, a moonlighting protein, as a potential target for cancer treatment. Int J Biol Sci. 17:3981–3992. 2021.PubMed/NCBI View Article : Google Scholar | |
|
Hu T, Liu H, Liang Z, Wang F, Zhou C, Zheng X, Zhang Y, Song Y, Hu J, He X, et al: Tumor-intrinsic CD47 signal regulates glycolysis and promotes colorectal cancer cell growth and metastasis. Theranostics. 10:4056–4072. 2020.PubMed/NCBI View Article : Google Scholar | |
|
Gu J, Zhong K, Wang L, Ni H, Zhao Y, Wang X, Yao Y, Jiang L, Wang B and Zhu X: ENO1 contributes to 5-fluorouracil resistance in colorectal cancer cells via EMT pathway. Front Oncol. 12(1013035)2022.PubMed/NCBI View Article : Google Scholar | |
|
Zhan P, Wang Y, Zhao S, Liu C, Wang Y, Wen M, Mao JH, Wei G and Zhang P: FBXW7 negatively regulates ENO1 expression and function in colorectal cancer. Lab Inves. 95:995–1004. 2015.PubMed/NCBI View Article : Google Scholar | |
|
Ahmad R, Singh JK, Wunnava A, Al-Obeed O, Abdulla M and Srivastava SK: Emerging trends in colorectal cancer: Dysregulated signaling pathways (review). Int J Mol Med. 47(14)2021.PubMed/NCBI View Article : Google Scholar | |
|
Leiphrakpam PD, Rajappa SJ, Krishnan M, Batra R, Murthy SS and Are C: Colorectal cancer: Review of signaling pathways and associated therapeutic strategies. J Surg Oncol. 127:1277–1295. 2023.PubMed/NCBI View Article : Google Scholar | |
|
Martini M, De Santis MC, Braccini L, Gulluni F and Hirsch E: PI3K/AKT signaling pathway and cancer: An updated review. Ann Med. 46:372–383. 2014.PubMed/NCBI View Article : Google Scholar | |
|
Yu H, Lee H, Herrmann A, Buettner R and Jove R: Revisiting STAT3 signalling in cancer: New and unexpected biological functions. Nat Rev Cancer. 14:736–746. 2014.PubMed/NCBI View Article : Google Scholar | |
|
Li D, Wang G, Jin G, Yao K, Zhao Z, Bie L, Guo Y, Li N, Deng W, Chen X, et al: Resveratrol suppresses colon cancer growth by targeting the AKT/STAT3 signaling pathway. Int J Mol Med. 43:630–640. 2019.PubMed/NCBI View Article : Google Scholar | |
|
Xue J, Ge X, Zhao W, Xue L, Dai C, Lin F and Peng W: PIPKIγ regulates CCL2 expression in colorectal cancer by activating AKT-STAT3 signaling. J Immunol Res. 2019(3690561)2019.PubMed/NCBI View Article : Google Scholar | |
|
Sun L, Lu T, Tian K, Zhou D, Yuan J, Wang X, Zhu Z, Wan D, Yao Y, Zhu X and He S: Alpha-enolase promotes gastric cancer cell proliferation and metastasis via regulating AKT signaling pathway. Eur J Pharmacol. 845:8–15. 2019.PubMed/NCBI View Article : Google Scholar | |
|
Fuhr L, El-Athman R, Scrima R, Cela O, Carbone A, Knoop H, Li Y, Hoffmann K, Laukkanen MO, Corcione F, et al: The circadian clock regulates metabolic phenotype rewiring via HKDC1 and modulates tumor progression and drug response in colorectal cancer. EBioMedicine. 33:105–121. 2018.PubMed/NCBI View Article : Google Scholar | |
|
Chen M, Tan AH and Li J: Curcumin represses colorectal cancer cell proliferation by triggering ferroptosis via PI3K/Akt/mTOR signaling. Nutr Cancer. 75:726–733. 2023.PubMed/NCBI View Article : Google Scholar | |
|
Wang Y, Zhang Z, Sun W, Zhang J, Xu Q, Zhou X and Mao L: Ferroptosis in colorectal cancer: Potential mechanisms and effective therapeutic targets. Biomed Pharmacother. 153(113524)2022.PubMed/NCBI View Article : Google Scholar | |
|
Duan L, Yang W, Wang X, Zhou W, Zhang Y, Liu J, Zhang H, Zhao Q, Hong L and Fan D: Advances in prognostic markers for colorectal cancer. Expert Rev Mol Diagn. 19:313–324. 2019.PubMed/NCBI View Article : Google Scholar | |
|
Deka D, Scarpa M, Das A, Pathak S and Banerjee A: Current understanding of epigenetics driven therapeutic strategies in colorectal cancer management. Endocr Metab Immune Disord Drug Targets. 21:1882–1894. 2021.PubMed/NCBI View Article : Google Scholar | |
|
Kim MS, Kim D and Kim JR: Stage-dependent gene expression profiling in colorectal cancer. IEEE/ACM Trans Comput Biol Bioinform. 16:1685–1692. 2019.PubMed/NCBI View Article : Google Scholar | |
|
Zhan P, Zhao S, Yan H, Yin C, Xiao Y, Wang Y, Ni R, Chen W, Wei G and Zhang P: α-Enolase promotes tumorigenesis and metastasis via regulating AMPK/mTOR pathway in colorectal cancer. Mol Carcinog. 56:1427–1437. 2017.PubMed/NCBI View Article : Google Scholar | |
|
Cheng Z, Shao X, Xu M, Zhou C and Wang J: ENO1 acts as a prognostic biomarker candidate and promotes tumor growth and migration ability through the regulation of Rab1A in colorectal cancer. Cancer Manag Res. 11:9969–9978. 2019.PubMed/NCBI View Article : Google Scholar | |
|
Finley LWS: What is cancer metabolism? Cell. 186:1670–1688. 2023.PubMed/NCBI View Article : Google Scholar | |
|
Ganapathy-Kanniappan S: Molecular intricacies of aerobic glycolysis in cancer: Current insights into the classic metabolic phenotype. Crit Rev Biochem Mol Biol. 53:667–682. 2018.PubMed/NCBI View Article : Google Scholar | |
|
Nenkov M, Ma Y, Gaßler N and Chen Y: Metabolic reprogramming of colorectal cancer cells and the microenvironment: Implication for therapy. Int J Mol Sci. 22(6262)2021.PubMed/NCBI View Article : Google Scholar | |
|
Zafari N, Velayati M, Damavandi S, Pourali G, Mobarhan MG, Nassiri M, Hassanian SM, Khazaei M, Ferns GA and Avan A: Metabolic pathways regulating colorectal cancer: A potential therapeutic approach. Curr Pharm Des. 28:2995–3009. 2022.PubMed/NCBI View Article : Google Scholar | |
|
Zhou J, Zhang S, Chen Z, He Z, Xu Y and Li Z: CircRNA-ENO1 promoted glycolysis and tumor progression in lung adenocarcinoma through upregulating its host gene ENO1. Cell Death Dis. 10(885)2019.PubMed/NCBI View Article : Google Scholar | |
|
He Y, Liu Y, Wu D, Chen L, Luo Z, Shi X, Li K, Hu H, Qu G, Zhao Q and Lian C: Linc-UROD stabilizes ENO1 and PKM to strengthen glycolysis, proliferation and migration of pancreatic cancer cells. Transl Oncol. 27(101583)2023.PubMed/NCBI View Article : Google Scholar | |
|
Qian X, Xu W, Xu J, Shi Q, Li J, Weng Y, Jiang Z, Feng L, Wang X, Zhou J and Jin H: Enolase 1 stimulates glycolysis to promote chemoresistance in gastric cancer. Oncotarget. 8:47691–47708. 2017.PubMed/NCBI View Article : Google Scholar | |
|
Kooshki L, Mahdavi P, Fakhri S, Akkol EK and Khan H: Targeting lactate metabolism and glycolytic pathways in the tumor microenvironment by natural products: A promising strategy in combating cancer. Biofactors. 48:359–383. 2022.PubMed/NCBI View Article : Google Scholar | |
|
Cao S, Chen Y, Ren Y, Feng Y and Long S: GLUT1 biological function and inhibition: research advances. Future Med Chem. 13:1227–1243. 2021.PubMed/NCBI View Article : Google Scholar | |
|
Li Z and Zhang H: Reprogramming of glucose, fatty acid and amino acid metabolism for cancer progression. Cell Mol Life Sci. 73:377–392. 2016.PubMed/NCBI View Article : Google Scholar | |
|
Jiang X, Stockwell BR and Conrad M: Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol. 22:266–282. 2021.PubMed/NCBI View Article : Google Scholar | |
|
Gao M, Yi J, Zhu J, Minikes AM, Monian P, Thompson CB and Jiang X: Role of mitochondria in ferroptosis. Mol Cell. 73:354–363.e3. 2019.PubMed/NCBI View Article : Google Scholar | |
|
Yang L, Zhang Y, Zhang Y and Fan Z: Mechanism and application of ferroptosis in colorectal cancer. Biomed Pharmacother. 158(114102)2023.PubMed/NCBI View Article : Google Scholar | |
|
Zhang T, Sun L, Hao Y, Suo C, Shen S, Wei H, Ma W, Zhang P, Wang T, Gu X, et al: ENO1 suppresses cancer cell ferroptosis by degrading the mRNA of iron regulatory protein 1. Nat Cancer. 3:75–89. 2022.PubMed/NCBI View Article : Google Scholar | |
|
Asantewaa G and Harris IS: Glutathione and its precursors in cancer. Curr Opin Biotechnol. 68:292–299. 2021.PubMed/NCBI View Article : Google Scholar | |
|
Tsikas D: Assessment of lipid peroxidation by measuring malondialdehyde (MDA) and relatives in biological samples: Analytical and biological challenges. Anal Biochem. 524:13–30. 2017.PubMed/NCBI View Article : Google Scholar | |
|
Zhang F, Li Z, Gao P, Zou J, Cui Y, Qian Y, Gu R, Xu W and Hu J: HJ11 decoction restrains development of myocardial ischemia-reperfusion injury in rats by suppressing ACSL4-mediated ferroptosis. Front Pharmacol. 13(1024292)2022.PubMed/NCBI View Article : Google Scholar | |
|
Hao J, Zhang W and Huang Z: Bupivacaine modulates the apoptosis and ferroptosis in bladder cancer via phosphatidylinositol 3-kinase (PI3K)/AKT pathway. Bioengineered. 13:6794–6806. 2022.PubMed/NCBI View Article : Google Scholar | |
|
Wang D, Jin X, Lei M, Jiang Y, Liu Y, Yu F, Guo Y, Han B, Yang Y, Sun W, et al: USF1-ATRAP-PBX3 axis promote breast cancer glycolysis and malignant phenotype by activating AKT/mTOR signaling. Int J Biol Sci. 18:2452–2471. 2022.PubMed/NCBI View Article : Google Scholar | |
|
Chen Y, Wang F, Wu P, Gong S, Gao J, Tao H, Shen Q, Wang S, Zhou Z and Jia Y: Artesunate induces apoptosis, autophagy and ferroptosis in diffuse large B cell lymphoma cells by impairing STAT3 signaling. Cell Signal. 88(110167)2021.PubMed/NCBI View Article : Google Scholar | |
|
Li YJ, Zhang C, Martincuks A, Herrmann A and Yu H: STAT proteins in cancer: orchestration of metabolism. Nat Rev Cancer. 23:115–134. 2023.PubMed/NCBI View Article : Google Scholar | |
|
Sun Z, Jiang Q, Gao B, Zhang X, Bu L, Wang L, Lin Y, Xie W, Li J and Guo J: AKT blocks SIK1-mediated repression of STAT3 to promote breast tumorigenesis. Cancer Res. 83:1264–1279. 2023.PubMed/NCBI View Article : Google Scholar | |
|
Li M, Zhao X, Yong H, Xu J, Qu P, Qiao S, Hou P, Li Z, Chu S, Zheng J and Bai J: Transketolase promotes colorectal cancer metastasis through regulating AKT phosphorylation. Cell Death Dis. 13(99)2022.PubMed/NCBI View Article : Google Scholar | |
|
Li Y, Wang Y, Liu Z, Guo X, Miao Z and Ma S: Atractylenolide I induces apoptosis and suppresses glycolysis by blocking the JAK2/STAT3 signaling pathway in colorectal cancer cells. Front Pharmacol. 11(273)2020.PubMed/NCBI View Article : Google Scholar | |
|
Zhao X and Chen F: Propofol induces the ferroptosis of colorectal cancer cells by downregulating STAT3 expression. Oncol Lett. 22(767)2021.PubMed/NCBI View Article : Google Scholar |
