GLRX Inhibition Enhances the Effects of Geftinib in EGFR-TKI-resistant NSCLC Cells Through FoxM1 Signaling Pathway

Overview

Journal J Cancer Res Clin Oncol

Specialty Oncology

Date 2019 Jan 21

PMID 30661098

Citations 5

Authors

Linlin Wang

Jing Liu

Jinguo Liu

Xiaoyan Chen

Meijia Chang

Jing Li

Jian Zhou

Chunxue Bai

Yuanlin Song

Affiliations

Soon will be listed here.

Abstract

Purpose: Non-small-cell lung cancer (NSCLC) is the most common form of lung cancer. Gefitinib is one of the most accepted therapies against NSCLC in those carrying EGFR mutations, but it is only effective in approximately 20% of patients with NSCLC. Thus, alternative therapeutic interventions are urgently needed to overcome gefitinib resistance. Glutaredoxin (GLRX) plays a key role in oxidative stress. However, whether GLRX inhibition could enhance gefitinib efficacy in the gefitinib-resistant NSCLC cells is unknown. In this study, we aimed to determine whether combined inhibition of GLRX could enhance growth-inhibitory effects of gefitinib in gefitinib-resistant NSCLC cells.

Methods: Real-time PCR and western blotting were used to examine the mRNA and protein levels of GLRX in gefitinib-sensitive PC9 and HCC827 and -resistant human lung adenocarcinoma PC9R, HCC827R, and H1975 cells. Cell Counting Kit-8, flow cytometry, JC-1 staining, and reactive oxygen species (ROS) assays were used to evaluate cell proliferation, cell cycle progression, mitochondrial membrane potential, and ROS generation, respectively. Mouse tumor xenografts were used to assess the effect of GLRX in vivo.

Results: We found that GLRX was upregulated in gefitinib-resistant PC9R, HCC827R, and H1975 cells. GLRX inhibition enhanced the effects of geftinib in gefitinib-resistant cell proliferation in vitro and in vivo and promoted apoptosis and cell cycle arrest via the EGFR/Forkhead Box M1 (FoxM1) signaling pathway, indicating that combined inhibition of GLRX could enhance growth-inhibitory effects of gefitinib in gefitinib-resistant NSCLC cells.

Conclusions: Our results suggest that GLRX inhibition enhances the effects of geftinib in EGFR-TKI-resistant NSCLC cells. Thus, GLRX may represent a therapeutic target for increasing the efficiency of gefitinib treatment.

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References

Chan K, Han X, Kan Y . An important function of Nrf2 in combating oxidative stress: detoxification of acetaminophen. Proc Natl Acad Sci U S A. 2001; 98(8):4611-6. PMC: 31882. DOI: 10.1073/pnas.081082098. View

Lundberg M, Johansson C, Chandra J, Enoksson M, Jacobsson G, Ljung J . Cloning and expression of a novel human glutaredoxin (Grx2) with mitochondrial and nuclear isoforms. J Biol Chem. 2001; 276(28):26269-75. DOI: 10.1074/jbc.M011605200. View

Gladyshev V, Liu A, Novoselov S, Krysan K, Sun Q, Kryukov V . Identification and characterization of a new mammalian glutaredoxin (thioltransferase), Grx2. J Biol Chem. 2001; 276(32):30374-80. DOI: 10.1074/jbc.M100020200. View

Nicholson R, Gee J, Harper M . EGFR and cancer prognosis. Eur J Cancer. 2001; 37 Suppl 4:S9-15. DOI: 10.1016/s0959-8049(01)00231-3. View

Wakeling A, Guy S, Woodburn J, Ashton S, Curry B, Barker A . ZD1839 (Iressa): an orally active inhibitor of epidermal growth factor signaling with potential for cancer therapy. Cancer Res. 2002; 62(20):5749-54. View

Ewald J, Wilkinson J, Guyer C, Staros J . Ligand- and kinase activity-independent cell survival mediated by the epidermal growth factor receptor expressed in 32D cells. Exp Cell Res. 2003; 282(2):121-31. DOI: 10.1016/s0014-4827(02)00014-9. View

Nagy P, Arndt-Jovin D, Jovin T . Small interfering RNAs suppress the expression of endogenous and GFP-fused epidermal growth factor receptor (erbB1) and induce apoptosis in erbB1-overexpressing cells. Exp Cell Res. 2003; 285(1):39-49. DOI: 10.1016/s0014-4827(02)00050-2. View

Fresno Vara J, Casado E, de Castro J, Cejas P, Belda-Iniesta C, Gonzalez-Baron M . PI3K/Akt signalling pathway and cancer. Cancer Treat Rev. 2004; 30(2):193-204. DOI: 10.1016/j.ctrv.2003.07.007. View

Le X, Pruefer F, Bast Jr R . HER2-targeting antibodies modulate the cyclin-dependent kinase inhibitor p27Kip1 via multiple signaling pathways. Cell Cycle. 2004; 4(1):87-95. DOI: 10.4161/cc.4.1.1360. View

10.

Nelson M, Dolder C . Lapatinib: a novel dual tyrosine kinase inhibitor with activity in solid tumors. Ann Pharmacother. 2006; 40(2):261-9. DOI: 10.1345/aph.1G387. View

11.

Feng F, Varambally S, Tomlins S, Chun P, Lopez C, Li X . Role of epidermal growth factor receptor degradation in gemcitabine-mediated cytotoxicity. Oncogene. 2006; 26(23):3431-9. DOI: 10.1038/sj.onc.1210129. View

12.

Yamanaka S, Gu Z, Sato M, Fujisaki R, Inomata K, Sakurada A . siRNA targeting against EGFR, a promising candidate for a novel therapeutic application to lung adenocarcinoma. Pathobiology. 2008; 75(1):2-8. DOI: 10.1159/000113789. View

13.

Weihua Z, Tsan R, Huang W, Wu Q, Chiu C, Fidler I . Survival of cancer cells is maintained by EGFR independent of its kinase activity. Cancer Cell. 2008; 13(5):385-93. PMC: 2413063. DOI: 10.1016/j.ccr.2008.03.015. View

14.

Gallogly M, Starke D, Mieyal J . Mechanistic and kinetic details of catalysis of thiol-disulfide exchange by glutaredoxins and potential mechanisms of regulation. Antioxid Redox Signal. 2009; 11(5):1059-81. PMC: 2842129. DOI: 10.1089/ars.2008.2291. View

15.

Park H, Carr J, Wang Z, Nogueira V, Hay N, Tyner A . FoxM1, a critical regulator of oxidative stress during oncogenesis. EMBO J. 2009; 28(19):2908-18. PMC: 2760115. DOI: 10.1038/emboj.2009.239. View

16.

Rho J, Choi Y, Lee J, Ryoo B, Na I, Yang S . The role of MET activation in determining the sensitivity to epidermal growth factor receptor tyrosine kinase inhibitors. Mol Cancer Res. 2009; 7(10):1736-43. DOI: 10.1158/1541-7786.MCR-08-0504. View

17.

Gallogly M, Shelton M, Qanungo S, Pai H, Starke D, Hoppel C . Glutaredoxin regulates apoptosis in cardiomyocytes via NFkappaB targets Bcl-2 and Bcl-xL: implications for cardiac aging. Antioxid Redox Signal. 2009; 12(12):1339-53. PMC: 2864653. DOI: 10.1089/ars.2009.2791. View

18.

Pao W, Chmielecki J . Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nat Rev Cancer. 2010; 10(11):760-74. PMC: 3072803. DOI: 10.1038/nrc2947. View

19.

Elzagallaai A, Garcia-Bournissen F, Finkelstein Y, Bend J, Rieder M, Koren G . Severe bullous hypersensitivity reactions after exposure to carbamazepine in a Han-Chinese child with a positive HLA-B*1502 and negative in vitro toxicity assays: evidence for different pathophysiological mechanisms. J Popul Ther Clin Pharmacol. 2011; 18(1):e1-9. View

20.

Yu J, Deshmukh H, Payton J, Dunham C, Scheithauer B, Tihan T . Array-based comparative genomic hybridization identifies CDK4 and FOXM1 alterations as independent predictors of survival in malignant peripheral nerve sheath tumor. Clin Cancer Res. 2011; 17(7):1924-34. DOI: 10.1158/1078-0432.CCR-10-1551. View