Hyperoside exhibits anticancer activity in non‑small cell lung cancer cells with T790M mutations by upregulating FoxO1 via CCAT1

  • Authors:
    • Zhiyuan Hu
    • Pengjun Zhao
    • Huifang Xu
  • View Affiliations

  • Published online on: December 18, 2019     https://doi.org/10.3892/or.2019.7440
  • Pages: 617-624
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Acquired epidermal growth factor receptor (EGFR) T790M mutation is the most common mechanism that accounts for EGFR‑TKI (tyrosine kinase inhibitor) resistance of non‑small cell lung cancer (NSCLC). High expense and acquired resistance weaken support for the use of osimertinib for T790M‑positive NSCLC treatment, and limit the efficacy and application of this drug. Hyperoside, a flavonol glycoside compound, extracted from Hypericum perforatum, has been reported to inhibit the growth of a variety of tumors. The present study aimed to investigate the role of hyperoside in treating NSCLC with T790M mutations, and to elucidate the underlying molecular mechanisms. Cell viability assays, apoptosis analysis, reverse transcription‑quantitative PCR, western blot analysis, animal experiments and immunohistochemistry were performed to examine the anticancer activity of hyperoside. Hyperoside inhibited the proliferation and induced the apoptosis of T790M‑positive NSCLC cells. Hyperoside upregulated forkhead box protein O1 (FoxO1) expression and downregulated the level of long non‑coding RNA (lncRNA) colon cancer associated transcript 1 (CCAT1) in T790M‑positive NSCLC cells. In the in vivo study, hyperoside inhibited the growth of T790M‑positive NSCLC xenografts. In conclusion, hyperoside inhibited proliferation and induced apoptosis by upregulating FoxO1 via CCAT1 in T790M‑positive NSCLC both in vitro and in vivo, suggesting that hyperoside is a novel candidate for T790M‑positive NSCLC treatment.

Introduction

Epidermal growth factor receptor (EGFR) mutations have been reported to play a vital role in the oncogenesis of non-small cell lung cancer (NSCLC). Exon 19 deletion and exon 21 L858R point mutations are the most common mutations associated with a positive response to first- and second-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs), and improved progression-free survival, compared with conventional chemotherapy (1). However, although patients show an initial response to EGFR-TKIs, the development of acquired resistance may appear after 9–14 months (2). The mechanisms underlying acquired resistance to first- and second-generation EGFR-TKIs include EGFR T790M secondary mutation, MET amplification, IGF1R activation, HGF overexpression, BRAF V600E mutation and epithelial-mesenchymal transition (EMT) (35). Among them, the acquired T790M mutation is the most common mechanism that accounts for more than 50% of resistant cases. Osimertinib, a third-generation EGFR-TKI, was developed to overcome T790M-positive NSCLC that obtained acquired resistance to EGFR-TKIs. Currently, osimertinib is the only drug approved by the Food and Drug Administration for T790M-positive NSCLC treatment, but with high financial cost (6). On the other hand, resistance to osimertinib has been reported (7). Such findings weaken the support for the use of osimertinib for T790M-positive NSCLC treatment and limit the efficacy and application of this drug. Therefore, it is necessary to search for an anti-T790M-positive NSCLC agent that exhibits high efficacy and low economic cost to the patient.

The development of anticancer agents from herbs has emerged as a novel strategy for potential cancer treatment and these agents show desirable efficacy with fewer adverse effects and low cost. These agents have been reported to present specific anti-proliferative, chemo-sensitizing or radio-sensitizing effects in various types of malignancies by targeting multiple signaling pathways (818). Hyperoside, a flavonol glycoside compound, extracted from Hypericum perforatum, is cultivated worldwide. Hyperoside has been studied extensively due to its anti-inflammatory, anti-oxidative, analgesic and anticancer activities. Hyperoside has been reported to inhibit the growth of a variety of malignancies, including lung cancer, colorectal cancer, pancreatic cancer, renal cancer, ovarian cancer, prostate cancer and osteosarcoma, without severe side effects and drug resistance (1925).

Recent studies have demonstrated that hyperoside inhibited lung cancer cell proliferation by inducing cell cycle arrest, autophagy and apoptosis through multiple signaling pathways (26,27). However, to the best of our knowledge, the anticancer effect of hyperoside on NSCLC with T790M mutation, and the underlying molecular mechanisms, have not been previously investigated. The present study investigated the anticancer activity of hyperoside in T790M-positive NSCLC cells and a xenograft model, and aimed to elucidate the underlying molecular mechanisms. In addition, the anticancer potential of hyperoside as a novel candidate for T790M-positive NSCLC treatment was investigated, and the associated target signaling pathway was identified.

Materials and methods

Drugs and cell lines

Hyperoside (C21H20O12) (Fig. 1) was obtained from Sigma-Aldrich; Merck KGaA (batch no. 00180585). The adenocarcinoma lung cancer cell line PC-9 and the T790M-positive NSCLC cell line NCI-H1975 were obtained from the Cell Bank of the Chinese Academy of Science (Shanghai, China). Cells were maintained in RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS; Thermo Fisher Scientific, Inc.) in a humidified atmosphere containing 5% CO2 at 37°C (seeding density: 4×104 cells/cm2, subculture every 4–5 days, 1:5 split).

Cell viability assay

Cells were plated into 96-well plates at a density of 5×103 cells per well. After incubation with different concentrations of hyperoside (0, 30, 60, 90, 120 and 150 µM) for 24, 48 and 72 h, MTT reagent (Sigma-Aldrich; Merck KGaA) was added and the cells were incubated for another 4 h. The supernatant was then replaced by dimethyl sulfoxide and the absorbance was detected at 490 nm using a microplate reader (Thermo Fisher Scientific, Inc.). Cell viability curves were generated.

For the clonogenic assay, cells were plated into 6-well plates at a density of 1×103 cells per well. Cells were treated with hyperoside (0, 30, 60, 90, 120 and 150 µM) for 48 h and further cultured in a humidified atmosphere containing 5% CO2 at 37°C for 14 days. The colonies were then fixed with paraformaldehyde prior to 0.5% crystal violet staining for 30 min at room temperature. Colonies were counted using an inverted light microscope (magnification, ×200; Olympus Corp.).

Apoptosis analysis

Cells were plated into 6-well plates at a density of 1×104 cells per well. After incubation with different concentrations of hyperoside (0, 30, 60, 90, 120 and 150 µM) for 48 h, the cells were trypsinized, washed and collected for apoptosis detection by flow cytometry. Annexin V-FITC and propidium iodide (Sigma-Aldrich; Merck KGaA) were added and the cells were incubated in the dark at 37°C for 15 min. Cell apoptotic rates were detected using a FACSCalibur flow cytometer.

Reverse transcription-quantitative PCR (RT-qPCR)

Total RNA was extracted from cells and xenograft tumor specimens using TRIzol® reagent (Thermo Fisher Scientific, Inc.) according to the manufacturer's protocol. The total RNA was reverse transcribed into complementary DNA using a PrimeScript RT reagent kit (Takara). PCR amplification was performed using a SYBR premix Taq kit (Takara). The primer sequences used were as follows: CCAT1: Forward, 5′-CATTGGGAAAGGTGCCGAGA-3′ and reverse, 5′-ACGCTTAGCCATACAGAGCC-3′; FoxO1: Forward, 5′-AGGATCCGATGTCACCATGGCCG-3′ and reverse, 5′-AAAGGATCCACCATGGCCG-3′. Amplification conditions for relative expression analysis were as follows: Denaturation at 95°C for 2 min; 40 cycles of 98°C for 20 sec, 55°C for 20 sec, and 68°C for 30 sec, and finally extension at 72°C for 4 min. All RT-qPCR reactions were performed using the ABI StepOne™ Real-Time PCR system (Applied Biosystems; Thermo Fisher Scientific, Inc.). The relative gene expression was calculated using the 2−ΔΔCq method and normalized to β-actin (28).

Western blot analysis

Total protein was extracted from cells with RIPA buffer. The protein concentration was quantified using a BCA Protein Assay kit. Equal amounts of protein were separated by 10% SDS-PAGE gel electrophoresis and transferred to polyvinylidene difluoride membranes. The membranes were blocked in TBST with 5% non-fat milk at 37°C for 2 h, followed by incubation with primary antibody (FoxO1; C29H4; rabbit monoclonal antibody; cat. no. 2880; dilution 1:1,000; Cell Signaling Technology, Inc.) at 4°C overnight. The membranes were washed with TBST and further incubated with horseradish peroxidase-conjugated secondary antibody (anti-rabbit IgG, cat. no. 7074; dilution 1:10,000; Cell Signaling Technology, Inc.) at 37°C for 1 h. Enhanced chemiluminescence was used to detect protein bands (Image Lab version 5.2; Bio-Rad Laboratories, Inc.). GAPDH was used as the endogenous control.

Cell transfection

Short hairpin RNA (shRNA) that specifically targets lncRNA colon cancer associated transcript 1 (CCAT1) or forkhead box protein O1 (FoxO1) (shCCAT1, shFoxO1) and amplified full-length CCAT1 or FoxO1 cDNA for overexpression (CCAT1, FoxO1) were synthesized by Genechem. The primer sequences used were as follows: shCCAT1-1, CCATTCCATTCATTTCTCTTTCCTA and shCCAT1-2, CAUACCAAUUGAACCGAGCCUUGUA; shFoxO1, GCTGCATGCTACCACCTTACA. The cells in the logarithmic growth phase were collected and then cultured in 6-well plates for transfection. Cell transfection was performed using lentivirus according to the manufacturer's protocols. Cells were transfected with lentiviral plasmid and particles (Sino Biological, Inc.), and then harvested for further evaluation at 48 h after transfection. RT-qPCR was performed in order to determine the transfection efficiency.

Animal experiment

Ten nude male mice of 4 weeks of age (weight 20±1 g) were purchased from SLAC Laboratory Animal, Co. H1975 cells, at a density of 1×106, were collected and subcutaneously injected into the flank of mice to form xenograft tumors. The mice were were randomly divided into a hyperoside group and a control group, and injected with hyperoside (25 mg/kg) once daily for 3 weeks, or injected with saline intraperitoneally once daily. The tumor volume was calculated as: Volume (mm3) = width2 (mm2) × length (mm) ÷ 2. Mice were sacrificed by cervical dislocation after 3 weeks, and the tumors were removed and weighed. The animal experimental procedures were approved by the Ethics Committee of Zhejiang Hospital and were in accordance with the National Institutes of Health Guidelines for Animal Care and Use (https://www.nap.edu/read/5140/chapter/1).

Immunohistochemistry

Briefly, tumor specimen sections were cut into 4-µm-thick sections and used for immunohistochemistry staining according to the manufacturer's protocol (Cell Signaling Technology, Inc.). Sections were deparaffinized and rehydrated. Incubation with the primary antibody (FoxO1; C29H4; rabbit monoclonal antibody; cat. no. 2880; dilution 1:1,00; Cell Signaling Technology, Inc.) was performed at 4°C overnight, and the sections were then incubated with secondary antibody [SignalStain® Boost IHC Detection Reagent (HRP, rabbit) cat. no. 8114; Cell Signaling Technology, Inc.)] for 30 min at room temperature, followed by DAB staining. Positive cells that exhibited brownish-yellow or tan coloring were scored (the staining intensity was scored as 0 (negative-weak), 1 (medium), 2 (strong), or 3 (very strong). The percentage of the staining area was scored as 0 (0–10%), 1 (11–50%), and 2 (51–100%) relative to the total tumor area) and observed under light microscopy (magnification, ×200; Olympus Corp.).

Statistical analysis

The data are presented as the mean ± standard deviation. One-way ANOVA followed by SNK-q post hoc test was performed using SPSS software (version 17.0; SPSS Inc.). P<0.05 was considered to indicate a statistically significant difference.

Results

Hyperoside inhibits the proliferation of T790M-positive NSCLC cells

H1975 cells were exposed to increasing doses of hyperoside (0–150 µM) for 24, 48 and 72 h and the cell viability was assessed by MTT assay. The viability of H1975 cells was significantly inhibited following hyperoside treatment in a dose- and time-dependent manner (Fig. 2A). The IC50 values of hyperoside at 24, 48 and 72 h were 104.1, 87.4 and 70.6 µM, respectively. Clonogenic assay was further performed to confirm the anti-proliferative activity of hyperoside, and the results revealed that hyperoside significantly inhibited the clonogenic ability of H1975 cells in a dose-dependent manner at 48 h (Fig. 2B and C). These data indicated that hyperoside effectively inhibited the growth of T790M-positive NSCLC.

Hyperoside induces the apoptosis of T790M-positive NSCLC cells

Flow cytometric analysis was performed in order to quantify the cellular apoptosis of H1975 cells induced by hyperoside. H1975 cells were exposed to increasing doses of hyperoside (0–150 µM) for 48 h, stained with Annexin V and PI and subjected to flow cytometry. The results revealed that hyperoside treatment led to a significant increase in the apoptosis rate in a dose-dependent manner when compared with the control group (Fig. 2D and E). These findings indicated that cell proliferation suppression by hyperoside was associated with the induction of apoptosis.

Hyperoside upregulates FoxO1 expression and downregulates the level of CCAT1 in T790M-positive NSCLC cells

In order to investigate the potential mechanisms underlying hyperoside in suppressing proliferation and inducing apoptosis in H1975 cells, western blotting and RT-qPCR assays were performed to examine the forkhead box protein O1 (FoxO1) protein expression levels and the level of long non-coding RNA (lncRNA) colon cancer associated transcript 1 (CCAT1). FoxO1 is a key protein that plays a crucial role in tumor cell apoptosis, and the results of the present study revealed that the expression of FoxO1 was downregulated and CCAT1 was upregulated in the T790M-positive H1975 cells compared with the wild-type PC-9 cells (Fig. S1). However, FoxO1 protein expression was observed to be upregulated following hyperoside (150 µM) treatment (Fig. 3A) in the H1975 cells, demonstrating that hyperoside-induced apoptosis was associated with FoxO1 upregulation. Meanwhile, hyperoside (150 µM) significantly downregulated the level of CCAT1 expression at 48 h (Fig. 3B). The present study further investigated whether CCAT1 regulates FoxO1 expression in T790M-positive H1975 cells. CCAT1 knockdown or overexpressing H1975 cells were established and the CCAT1 expression level was determined (Fig. 3C). It was revealed that FoxO1 protein expression was upregulated in the CCAT1-knockdown H1975 cells, while FoxO1 protein expression was downregulated in the CCAT1-overexpressing H1975 cells (Fig. 3D).

Hyperoside inhibits proliferation and induces apoptosis through upregulation of FoxO1 via CCAT1 in T790M-positive NSCLC cells

MTT assay and Annexin V/PI apoptosis analysis were performed in order to investigate the anticancer activity of hyperoside in CCAT1-knockdown or -overexpressing and FoxO1-knockdown or -overexpressing H1975 cells (Figs. 3C and 4A). The results revealed that hyperoside did not decrease the cell proliferation or increase the apoptosis rate in the CCAT1-overexpressing or FoxO1-knockdown H1975 cells (Fig. 4B and C), suggesting that CCAT1-mediated FoxO1 signaling was essential for hyperoside in treating T790M-positive NSCLC.

Hyperoside inhibits the growth of T790M-positive NSCLC xenografts

A xenograft tumor model was established by transplanting H1975 cells into nude mice in order to investigate the anticancer effect of hyperoside in vivo. Hyperoside significantly inhibited the growth of H1975 ×enograft tumors (Fig. 5A), and the nude mice did not exhibit significant weight loss in the hyperoside group compared with the control group (Fig. 5B). Finally, tumor tissues were removed and prepared for RT-qPCR analysis, immunohistochemistry staining and western blot analysis. The results revealed that FoxO1was highly expressed in the hyperoside group compared with the control group, and the level of CCAT1 was significantly downregulated by hyperoside treatment (Fig. 5C-E).

Discussion

Previous studies have demonstrated that hyperoside exhibits anticancer effects in various types of cancer cell lines by modulating multiple signaling pathways. Hyperoside was found to exert an inhibitory effect on lung cancer growth by inducing apoptosis and cell cycle arrest through phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK), activation of P53 signaling and caspase-3 and −9, and inhibition of NF-κB transcriptional activity (19,29,30). Hyperoside induced both autophagy and apoptosis in non-small cell lung cancer (NSCLC) cells by inhibiting the phosphorylation of Akt, mTOR, p70S6K and 4E-BP1, but increased the phosphorylation of ERK1/2 (27). Hyperoside was found to regulate microRNAs such as miR-21 or miR-27 to inhibit prostate or renal cancer growth and metastasis (23,24). However, to the best of our knowledge, the molecular mechanisms underlying hyperoside in treating T790M-positive NSCLC have not yet been elucidated.

Apoptosis is considered to be an important biological process in cell survival, and resisting apoptosis is one of the main hallmarks of carcinogenesis. Apoptosis is controlled by a variety of apoptotic-associated genes, and current evidence supports the fact that forkhead box protein O1 (FoxO1) is critical for cell survival (31). FoxO1, regarded as a tumor-suppressing factor, can inhibit carcinogenesis, while FoxO1 disruption may promote carcinogenesis. Activation of FoxO1 was found to trigger cancer cell apoptosis, leading to inhibition of tumor growth (32). The present study demonstrated that hyperoside inhibited proliferation and induced apoptosis in H1975 cells, and the suppression of cell proliferation by hyperoside was associated with the induction of apoptosis. Further investigation revealed that FoxO1 protein expression was upregulated as a result of hyperoside treatment, suggesting that the anticancer activity of hyperoside was associated with FoxO1 upregulation.

An increasing amount of evidence has demonstrated that lncRNAs, >200 nucleotides in length, play an important role in cellular biological processes, including carcinogenesis. lncRNAs, exerting gene transcription regulatory function, have been increasingly studied in cancer diagnosis and therapy. Notably, the aberrant expression of lncRNAs has been demonstrated to contribute to the development of cancer. lncRNA colon cancer associated transcript 1 (CCAT1), located on chromosome 8q24.21, was first observed as highly expressed in colorectal cancer. However, CCAT1 has been reported to be an oncogenic lncRNA and is upregulated in a variety of human cancer types, including lung cancer, gastric cancer, hepatocellular cancer, breast cancer, gallbladder cancer, ovarian cancer and acute myeloid leukemia (33). Particularly in NSCLC, it has been reported that aberrant CCAT1 expression may induce epithelial-to-mesenchymal transition (EMT) by regulating the expression levels of E-cadherin, N-cadherin and vimentin (34). CCAT1 was found to be upregulated in cisplatin-resistant NSCLC and contributed to cisplatin-resistance by downregulation of miR-130a-3p (35). CCAT1 was also found to contribute to docetaxel-resistance in lung adenocarcinoma, and CCAT1 downregulation decreased chemoresistance, promoted apoptosis and reversde the EMT phenotype of docetaxel-resistant cells (36). However, the expression levels of CCAT1 in T790M-positive NSCLC and whether this lncRNA is involved in the anticancer effects of hyperoside remain unclear. In the present study, it was revealed that hyperoside notably downregulated the level of CCAT1 expression. CCAT1 regulated the FoxO1 expression in H1975 cells. Hyperoside could not decrease cell proliferation or increase the apoptosis rate in CCAT1-overexpressing or FoxO1-knockdown H1975 cells, demonstrating that hyperoside inhibited T790M-positive NSCLC tumor growth and promoted apoptosis by upregulating FoxO1 via CCAT1.

In conclusion, the present study demonstrated that hyperoside inhibited proliferation and induced apoptosis by upregulating FoxO1 via CCAT1 in T790M-positive NSCLC cells, providing a theoretical basis for hyperoside in treating T790M-positive NSCLC. Further studies are required in order to apply hyperoside to the clinical setting.

Supplementary Material

Supporting Data

Acknowledgements

Not applicable.

Funding

The present study was supported by the Medical Technology Planning Program of Zhejiang Province (grant no. 2019KY507).

Availability of data and materials

The datasets used during the present study are available from the corresponding author upon reasonable request.

Authors' contributions

HX conceived and designed the study. ZH and PZ performed the experiments. ZH wrote the paper. HX reviewed and edited the manuscript. All authors read and approved the manuscript and agree to be accountable for all aspects of the research in ensuring that the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Ethics approval and consent to participate

The animal experimental procedures were approved by the Ethics Committee of Zhejiang Hospital and were in accordance with the National Institutes of Health Guidelines for Animal Care and Use.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References

1 

Shigematsu H and Gazdar AF: Somatic mutations of epidermal growth factor receptor signaling pathway in lung cancers. Int J Cancer. 118:257–262. 2006. View Article : Google Scholar : PubMed/NCBI

2 

Zhou C and Yao LD: Strategies to improve outcomes of patients with EGRF-mutant non-small cell lung cancer: Review of the literature. J Thorac Oncol. 11:174–186. 2016. View Article : Google Scholar : PubMed/NCBI

3 

Kobayashi S, Boggon TJ, Dayaram T, Jänne PA, Kocher O, Meyerson M, Johnson BE, Eck MJ, Tenen DG and Halmos B: EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 352:786–792. 2005. View Article : Google Scholar : PubMed/NCBI

4 

Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, Bergethon K, Shaw AT, Gettinger S, Cosper AK, et al: Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 3:75ra262011. View Article : Google Scholar : PubMed/NCBI

5 

Ohashi K, Maruvka YE, Michor F and Pao W: Epidermal growth factor receptor tyrosine kinase inhibitor-resistant disease. J Clin Oncol. 31:1070–1080. 2013. View Article : Google Scholar : PubMed/NCBI

6 

Remon J, Steuer CE, Ramalingam SS and Felip E: Osimertinib and other third-generation EGFR TKI in EGFR-mutant NSCLC patients. Ann Oncol. 29 (Suppl 1):i20–i27. 2018. View Article : Google Scholar : PubMed/NCBI

7 

Yang Z, Yang N, Ou Q, Xiang Y, Jiang T, Wu X, Bao H, Tong X, Wang X, Shao YW, et al: Investigating novel resistance mechanisms to third-generation EGFR tyrosine kinase inhibitor osimertinib in non-small cell lung cancer patients. Clin Cancer Res. 24:3097–3107. 2018. View Article : Google Scholar : PubMed/NCBI

8 

Jiang H, Zhao PJ, Su D, Feng J and Ma SL: Paris saponin I induces apoptosis via increasing the Bax/Bcl-2 ratio and caspase-3 expression in gefitinib-resistant non-small cell lung cancer in vitro and in vivo. Mol Med Rep. 9:2265–2272. 2014. View Article : Google Scholar : PubMed/NCBI

9 

Jiang H, Zhao P, Feng J, Su D and Ma S: Effect of Paris saponin I on radiosensitivity in a gefitinib-resistant lung adenocarcinoma cell line. Oncol Lett. 7:2059–2064. 2014. View Article : Google Scholar : PubMed/NCBI

10 

Zhao P, Jiang H, Su D, Feng J, Ma S and Zhu X: Inhibition of cell proliferation by mild hyperthermia at 43°C with Paris saponin I in the lung adenocarcinoma cell line PC-9. Mol Med Rep. 11:327–332. 2015. View Article : Google Scholar : PubMed/NCBI

11 

Zhu X, Jiang H, Li J, Xu J and Fei Z: Anticancer effects of Paris saponins by apoptosis and PI3K/AKT pathway in gefitinib-resistant non-small cell lung cancer. Med Sci Monit. 22:1435–1441. 2016. View Article : Google Scholar : PubMed/NCBI

12 

Zhao PJ, Song SC, Du LW, Zhou GH, Ma SL, Li JH, Feng JG, Zhu XH and Jiang H: Paris Saponins enhance radiosensitivity in a gefitinib-resistant lung adenocarcinoma cell line by inducing apoptosis and G2/M cell cycle phase arrest. Mol Med Rep. 13:2878–2884. 2016. View Article : Google Scholar : PubMed/NCBI

13 

Song S, Du L, Jiang H, Zhu X, Li J and Xu J: Paris Saponin I sensitizes gastric cancer cell lines to cisplatin via cell cycle arrest and apoptosis. Med Sci Monit. 22:3798–3803. 2016. View Article : Google Scholar : PubMed/NCBI

14 

Zheng R, Rao Y, Jiang H, Liu X, Zhu X, Li J and Xu J: Therapeutic potential of ginsenoside Rg3 via inhibiting Notch/HES1 pathway in lung cancer cells. Transl Cancer Res. 5:464–469. 2016. View Article : Google Scholar

15 

Zheng R, Jiang H, Li J, Liu X and Xu H: Polyphyllin II restores sensitization of the resistance of PC-9/ZD cells to gefitinib by a negative regulation of the PI3K/Akt/mTOR signaling pathway. Curr Cancer Drug Targets. 17:376–385. 2017. View Article : Google Scholar : PubMed/NCBI

16 

Wang H, Fei Z and Jiang H: Polyphyllin VII increases sensitivity to gefitinib by modulating the elevation of P21 in acquired gefitinib resistant non-small cell lung cancer. J Pharmacol Sci. 134:190–196. 2017. View Article : Google Scholar : PubMed/NCBI

17 

Yang Q, Chen W, Xu Y, Lv X, Zhang M and Jiang H: Polyphyllin I modulates MALAT1/STAT3 signaling to induce apoptosis in gefitinib-resistant non-small cell lung cancer. Toxicol Appl Pharmacol. 356:1–7. 2018. View Article : Google Scholar : PubMed/NCBI

18 

Hong F, Gu W, Jiang J, Liu X and Jiang H: Anticancer activity of polyphyllin I in nasopharyngeal carcinoma by modulation of lncRNA ROR and P53 signalling. J Drug Target. 27:806–811. 2019. View Article : Google Scholar : PubMed/NCBI

19 

Yang Y, Tantai J, Sun Y, Zhong C and Li Z: Effect of hyperoside on the apoptosis of A549 human non-small cell lung cancer cells and the underlying mechanism. Mol Med Rep. 16:6483–6488. 2017. View Article : Google Scholar : PubMed/NCBI

20 

Guon TE and Chung HS: Hyperoside and rutin of Nelumbo nucifera induce mitochondrial apoptosis through a caspase- dependent mechanism in HT-29 human colon cancer cells. Oncol Lett. 11:2463–2470. 2016. View Article : Google Scholar : PubMed/NCBI

21 

Boukes GJ and van de Venter M: The apoptotic and autophagic properties of two natural occurring prodrugs, hyperoside and hypoxoside, against pancreatic cancer cell lines. Biomed Pharmacother. 83:617–626. 2016. View Article : Google Scholar : PubMed/NCBI

22 

Zhu X, Ji M, Han Y, Guo Y, Zhu W, Gao F, Yang X and Zhang C: PGRMC1-dependent autophagy by hyperoside induces apoptosis and sensitizes ovarian cancer cells to cisplatin treatment. Int J Oncol. 50:835–846. 2017. View Article : Google Scholar : PubMed/NCBI

23 

Li W, Liu M, Xu YF, Feng Y, Che JP, Wang GC and Zheng JH: Combination of quercetin and hyperoside has anticancer effects on renal cancer cells through inhibition of oncogenic microRNA-27a. Oncol Rep. 31:117–124. 2014. View Article : Google Scholar : PubMed/NCBI

24 

Yang FQ, Liu M, Li W, Che JP, Wang GC and Zheng JH: Combination of quercetin and hyperoside inhibits prostate cancer cell growth and metastasis via regulation of microRNA-21. Mol Med Rep. 11:1085–1092. 2015. View Article : Google Scholar : PubMed/NCBI

25 

Zhang N, Ying MD, Wu YP, Zhou ZH, Ye ZM, Li H and Lin DS: Hyperoside, a flavonoid compound, inhibits proliferation and stimulates osteogenic differentiation of human osteosarcoma cells. PLoS One. 9:e989732014. View Article : Google Scholar : PubMed/NCBI

26 

Li JP, Liao XH, Xiang Y, Yao A, Song RH, Zhang ZJ, Huang F, Dai ZT and Zhang TC: Hyperoside and let-7a-5p synergistically inhibits lung cancer cell proliferation via inducing G1/S phase arrest. Gene. 679:232–240. 2018. View Article : Google Scholar : PubMed/NCBI

27 

Fu T, Wang L, Jin XN, Sui HJ, Liu Z and Jin Y: Hyperoside induces both autophagy and apoptosis in non-small cell lung cancer cells in vitro. Acta Pharmacol Sin. 37:505–518. 2016. View Article : Google Scholar : PubMed/NCBI

28 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI

29 

Liu YH, Liu GH, Mei JJ and Wang J: The preventive effects of hyperoside on lung cancer in vitro by inducing apoptosis and inhibiting proliferation through Caspase-3 and P53 signaling pathway. Biomed Pharmacother. 83:381–391. 2016. View Article : Google Scholar : PubMed/NCBI

30 

Lü P: Inhibitory effects of hyperoside on lung cancer by inducing apoptosis and suppressing inflammatory response via caspase-3 and NF-κB signaling pathway. Biomed Pharmacother. 82:216–225. 2016. View Article : Google Scholar : PubMed/NCBI

31 

Xing YQ, Li A, Yang Y, Li XX, Zhang LN and Guo HC: The regulation of FOXO1 and its role in disease progression. Life Sci. 193:124–131. 2018. View Article : Google Scholar : PubMed/NCBI

32 

Cosimo E, Tarafdar A, Moles MW, Holroyd AK, Malik N, Catherwood MA, Hay J, Dunn KM, Macdonald AM, Guichard SM, et al: AKT/mTORC2 inhibition activates FOXO1 function in CLL cells reducing B-cell receptor-mediated survival. Clin Cancer Res. 25:1574–1587. 2019. View Article : Google Scholar : PubMed/NCBI

33 

Guo X and Hua Y: CCAT1: An oncogenic long noncoding RNA in human cancers. J Cancer Res Clin Oncol. 143:555–562. 2017. View Article : Google Scholar : PubMed/NCBI

34 

Lin H, Cheng W, Yan H and Zhang X: Overexpression of the long noncoding RNA CCAT1 promotes metastasis via epithelial-to-mesenchymal transition in lung adenocarcinoma. Oncol Lett. 16:1809–1814. 2018.PubMed/NCBI

35 

Hu B, Zhang H, Wang Z, Zhang F, Wei H and Li L: LncRNA CCAT1/miR-130a-3p axis increases cisplatin resistance in non-small-cell lung cancer cell line by targeting SOX4. Cancer Biol Ther. 18:974–983. 2017. View Article : Google Scholar : PubMed/NCBI

36 

Chen J, Zhang K, Song H, Wang R, Chu X and Chen L: Long noncoding RNA CCAT1 acts as an oncogene and promotes chemoresistance in docetaxel-resistant lung adenocarcinoma cells. Oncotarget. 7:62474–62489. 2016.PubMed/NCBI

Related Articles

Journal Cover

February-2020
Volume 43 Issue 2

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
Hu Z, Zhao P and Xu H: Hyperoside exhibits anticancer activity in non‑small cell lung cancer cells with T790M mutations by upregulating FoxO1 via CCAT1. Oncol Rep 43: 617-624, 2020
APA
Hu, Z., Zhao, P., & Xu, H. (2020). Hyperoside exhibits anticancer activity in non‑small cell lung cancer cells with T790M mutations by upregulating FoxO1 via CCAT1. Oncology Reports, 43, 617-624. https://doi.org/10.3892/or.2019.7440
MLA
Hu, Z., Zhao, P., Xu, H."Hyperoside exhibits anticancer activity in non‑small cell lung cancer cells with T790M mutations by upregulating FoxO1 via CCAT1". Oncology Reports 43.2 (2020): 617-624.
Chicago
Hu, Z., Zhao, P., Xu, H."Hyperoside exhibits anticancer activity in non‑small cell lung cancer cells with T790M mutations by upregulating FoxO1 via CCAT1". Oncology Reports 43, no. 2 (2020): 617-624. https://doi.org/10.3892/or.2019.7440