Metformin impairs cisplatin resistance effects in A549 lung cancer cells through mTOR signaling and other metabolic pathways

Morelli,Ana Paula; Tortelli Jr,Tharcísio Citrângulo; Pavan,Isadora Carolina Betim; Silva,Fernando Riback; Granato,Daniela Campos; Peruca,Guilherme Francisco; Pauletti,Bianca Alves; Domingues,Romênia Ramos; Bezerra,Rosangela Maria Neves; De Moura,Leandro Pereira; Paes Leme,Adriana Franco; Chammas,Roger; Simabuco,Fernando Moreira

doi:10.3892/ijo.2021.5208

Metformin impairs cisplatin resistance effects in A549 lung cancer cells through mTOR signaling and other metabolic pathways

Authors:
- Ana Paula Morelli
- Tharcísio Citrângulo Tortelli Jr
- Isadora Carolina Betim Pavan
- Fernando Riback Silva
- Daniela Campos Granato
- Guilherme Francisco Peruca
- Bianca Alves Pauletti
- Romênia Ramos Domingues
- Rosangela Maria Neves Bezerra
- Leandro Pereira De Moura
- Adriana Franco Paes Leme
- Roger Chammas
- Fernando Moreira Simabuco
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Affiliations: Multidisciplinary Laboratory of Food and Health, School of Applied Sciences, State University of Campinas, Limeira, SP 13484‑350, Brazil, Centro de Investigação Translacional em Oncologia, Departamento de Radiologia e Oncologia, Faculdade de Medicina da Universidade de São Paulo and Instituto do Câncer do Estado de São Paulo, São Paulo, SP 04021‑001, Brazil, Laboratory of Signaling Mechanisms, School of Pharmaceutical Sciences, State University of Campinas, Campinas, SP 13083‑871, Brazil, Brazilian Biosciences National Laboratory, Brazilian Center for Research in Energy and Materials, Campinas, SP 13083‑970, Brazil, Exercise Cell Biology Laboratory, School of Applied Sciences, State University of Campinas, Limeira, SP 13484‑350, Brazil
Published online on: April 8, 2021 https://doi.org/10.3892/ijo.2021.5208
Article Number: 28
Copyright: © Morelli et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Lung cancer is the leading cause of cancer‑associated death worldwide and exhibits intrinsic and acquired therapeutic resistance to cisplatin (CIS). The present study investigated the role of mTOR signaling and other signaling pathways after metformin (MET) treatment in control and cisplatin‑resistant A549 cells, mapping pathways and possible targets involved in CIS sensitivity. MTT, flow cytometry, clonogenic assay, western blotting, proteomic analysis using the Stable Isotope Labeling by Amino acids in Cell culture (SILAC) approach and reverse transcription‑quantitative PCR were performed. The results revealed that CIS treatment induced mTOR signaling pathway overactivation, and the mTOR status was restored by MET. MET and the mTOR inhibitor rapamycin (RAPA) decreased the viability in control and resistant cells, and decreased the cell size increase induced by CIS. In control cells, MET and RAPA decreased colony formation after 72 h and decreased IC₅₀ values, potentiating the effects of CIS. Proteomics analysis revealed important pathways regulated by MET, including transcription, RNA processing and IL‑12‑mediated signaling. In CIS‑resistant cells, MET regulated the apoptotic process, oxidative stress and G₂/M transition. Annexin 4 (ANXA4) and superoxide dismutase 2 (SOD2), involved in apoptosis and oxidative stress, respectively, were chosen to validate the SILAC analysis and may represent potential therapeutic targets for lung cancer treatment. In conclusion, the chemosensitizing and antiproliferative effects of MET were associated with mTOR signaling and with potential novel targets, such as ANXA4 and SOD2, in human lung cancer cells.

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1	Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI
2	Ridge CA, McErlean AM and Ginsberg MS: Epidemiology of lung cancer. Semin Intervent Radiol. 30:93–98. 2013. View Article : Google Scholar :
3	Hirsch FR, Scagliotti GV, Mulshine JL, Kwon R, Curran WJ, Wu YL and Paz-Ares L: Lung cancer: Current therapies and new targeted treatments. Lancet. 389:299–311. 2017. View Article : Google Scholar
4	Talebian Yazdi M, Schinkelshoek MS, Loof NM, Taube C, Hiemstra PS, Welters MJ and van der Burg SH: Standard radiotherapy but not chemotherapy impairs systemic immunity in non-small cell lung cancer. Oncoimmunology. 5:e12553932016. View Article : Google Scholar
5	Sarin N, Engel F, Kalayda GV, Mannewitz M, Cinatl J Jr, Rothweiler F, Michaelis M, Saafan H, Ritter CA, Jaehde U and Frötschl R: Cisplatin resistance in non-small cell lung cancer cells is associated with an abrogation of cisplatin-induced G2/M cell cycle arrest. PLoS One. 12:e01810812017. View Article : Google Scholar : PubMed/NCBI
6	Yang Z, Hackshaw A, Feng Q, Fu X, Zhang Y, Mao C and Tang J: Comparison of gefitinib, erlotinib and afatinib in non-small cell lung cancer: A meta-analysis. Int J Cancer. 140:2805–2819. 2017. View Article : Google Scholar : PubMed/NCBI
7	Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L, et al: Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 372:2018–228. 2015. View Article : Google Scholar : PubMed/NCBI
8	Uchibori K, Inase N, Araki M, Kamada M, Sato S, Okuno Y, Fujita N and Katayama R: Brigatinib combined with anti-EGFR antibody overcomes osimertinib resistance in EGFR-mutated non-small-cell lung cancer. Nat Commun. 8:147682017. View Article : Google Scholar : PubMed/NCBI
9	Facchinetti F, Rossi G, Bria E, Soria JC, Besse B, Minari R, Friboulet L and Tiseo M: Oncogene addiction in non-small cell lung cancer: Focus on ROS1 inhibition. Cancer Treat Rev. 55:83–95. 2017. View Article : Google Scholar : PubMed/NCBI
10	Planchard D, Kim TM, Mazieres J, Quoix E, Riely G, Barlesi F, Souquet PJ, Smit EF, Groen HJ, Kelly RJ, et al: Dabrafenib in patients with BRAF(V600E)-positive advanced non-small-cell lung cancer: A single-arm, multicentre, open-label, phase 2 trial. Lancet Oncol. 17:642–650. 2016. View Article : Google Scholar : PubMed/NCBI
11	Herbst RS, Morgensztern D and Boshoff C: The biology and management of non-small cell lung cancer. Nature. 553:446–454. 2018. View Article : Google Scholar : PubMed/NCBI
12	Decensi A, Puntoni M, Goodwin P, Cazzaniga M, Gennari A, Bonanni B and Gandini S: Metformin and cancer risk in diabetic patients: A systematic review and meta-analysis. Cancer Prev Res (Phila). 3:1451–1461. 2010. View Article : Google Scholar
13	Cantrell LA, Zhou C, Mendivil A, Malloy KM, Gehrig PA and Bae-Jump VL: Metformin is a potent inhibitor of endometrial cancer cell proliferation-implications for a novel treatment strategy. Gynecol Oncol. 116:92–98. 2010. View Article : Google Scholar
14	Dong L, Zhou Q, Zhang Z, Zhu Y, Duan T and Feng Y: Metformin sensitizes endometrial cancer cells to chemotherapy by repressing glyoxalase I expression. J Obstet Gynaecol Res. 38:1077–1085. 2012. View Article : Google Scholar : PubMed/NCBI
15	Duo J, Ma Y, Wang G, Han X and Zhang C: Metformin synergistically enhances antitumor activity of histone deacetylase inhibitor trichostatin a against osteosarcoma cell line. DNA Cell Biol. 32:156–164. 2013. View Article : Google Scholar : PubMed/NCBI
16	Fujita H, Hirose K, Sato M, Fujioka I, Fujita T, Aoki M and Takai Y: Metformin attenuates hypoxia-induced resistance to cisplatin in the HepG2 cell line. Oncol Lett. 17:2431–2440. 2018.
17	Lin CC, Yeh HH, Huang WL, Yan JJ, Lai WW, Su WP, Chen HH and Su WC: Metformin enhances cisplatin cytotoxicity by suppressing signal transducer and activator of transcription-3 activity independently of the liver kinase B1-AMP-activated protein kinase pathway. Am J Respir Cell Mol Biol. 49:241–250. 2013. View Article : Google Scholar : PubMed/NCBI
18	Yu G, Fang W, Xia T, Chen Y, Gao Y, Jiao X, Huang S, Wang J, Li Z and Xie K: Metformin potentiates rapamycin and cisplatin in gastric cancer in mice. Oncotarget. 6:12748–1262. 2015. View Article : Google Scholar : PubMed/NCBI
19	Teixeira SF: Metformin synergistically enhances antiproliferative effects of cisplatin and etoposide in NCI-H460 human lung cancer cells. J Bras Pneumol. 39:644–649. 2013. View Article : Google Scholar
20	Li L, Han R, Xiao H, Lin C, Wang Y, Liu H, Li K, Chen H, Sun F, Yang Z, Jiang J and He Y: Metformin sensitizes EGFR-TKI-resistant human lung cancer cells in vitro and in vivo through inhibition of IL-6 signaling and EMT reversal. Clin Cancer Res. 20:2714–2726. 2014. View Article : Google Scholar : PubMed/NCBI
21	Li L, Wang Y, Peng T, Zhang K, Lin C, Han R, Lu C and He Y: Metformin restores crizotinib sensitivity in crizotinib-resistant human lung cancer cells through inhibition of IGF1-R signaling pathway. Oncotarget. 7:34442–34452. 2016. View Article : Google Scholar : PubMed/NCBI
22	Pernicova I and Korbonits M: Metformin-mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol. 10:143–156. 2014. View Article : Google Scholar : PubMed/NCBI
23	Liu GY and Sabatini DM: mTOR at the nexus of nutrition, growth, ageing and disease. Nat Rev Mol Cell Biol. 21:183–203. 2020. View Article : Google Scholar : PubMed/NCBI
24	Tavares MR, Pavan IC, Amaral CL, Meneguello L, Luchessi AD and Simabuco FM: The S6K protein family in health and disease. Life Sci. 131:1–10. 2015. View Article : Google Scholar : PubMed/NCBI
25	Magnuson B, Ekim B and Fingar DC: Regulation and function of ribosomal protein S6 kinase (S6K) within mTOR signalling networks. Biochem J. 441:1–21. 2012. View Article : Google Scholar
26	Amaral CL, Freitas LB, Tamura RE, Tavares MR, Pavan IC, Bajgelman MC and Simabuco FM: S6Ks isoforms contribute to viability, migration, docetaxel resistance and tumor formation of prostate cancer cells. BMC Cancer. 16:6022016. View Article : Google Scholar : PubMed/NCBI
27	Zhong D, Guo L, de Aguirre I, Liu X, Lamb N, Sun SY, Gal AA, Vertino PM and Zhou W: LKB1 mutation in large cell carcinoma of the lung. Lung Cancer. 53:285–294. 2006. View Article : Google Scholar : PubMed/NCBI
28	Kullmann L and Krahn MP: Controlling the master-upstream regulation of the tumor suppressor LKB1. Oncogene. 37:3045–3057. 2018. View Article : Google Scholar : PubMed/NCBI
29	Jiang G and Liu CT: Knockdown of SALL4 overcomes cisplatin-resistance through AKT/mTOR signaling in lung cancer cells. Int J Clin Exp Pathol. 11:634–641. 2018.PubMed/NCBI
30	Teng X, Fan XF, Li Q, Liu S, Wu DY, Wang SY, Shi Y and Dong M: XPC inhibition rescues cisplatin resistance via the Akt/mTOR signaling pathway in A549/DDP lung adenocarcinoma cells. Oncol Rep. 41:1875–1882. 2019.PubMed/NCBI
31	Liang SQ, Bührer ED, Berezowska S, Marti TM, Xu D, Froment L, Yang H, Hall SRR, Vassella E, Yang Z, et al: mTOR mediates a mechanism of resistance to chemotherapy and defines a rational combination strategy to treat KRAS-mutant lung cancer. Oncogene. 38:622–636. 2019. View Article : Google Scholar
32	Algire C, Amrein L, Bazile M, David S, Zakikhani M and Pollak M: Diet and tumor LKB1 expression interact to determine sensitivity to anti-neoplastic effects of metformin in vivo. Oncogene. 30:1174–1182. 2011. View Article : Google Scholar
33	Moro M, Caiola E, Ganzinelli M, Zulato E, Rulli E, Marabese M, Centonze G, Busico A, Pastorino U, de Braud FG, et al: Metformin enhances cisplatin-induced apoptosis and prevents resistance to cisplatin in Co-mutated KRAS/LKB1 NSCLC. J Thorac Oncol. 13:1692–1704. 2018. View Article : Google Scholar : PubMed/NCBI
34	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
35	Ye J, Coulouris G, Zaretskaya I, Cutcutache I, Rozen S and Madden TL: Primer-BLAST: A tool to design target-specific primers for polymerase chain reaction. BMC Bioinformatics. 13:1342012. View Article : Google Scholar : PubMed/NCBI
36	Bremang M, Cuomo A, Agresta AM, Stugiewicz M, Spadotto V and Bonaldi T: Mass spectrometry-based identification and characterisation of lysine and arginine methylation in the human proteome. Mol Biosyst. 9:2231–2247. 2013. View Article : Google Scholar : PubMed/NCBI
37	Cox J, Neuhauser N, Michalski A, Scheltema RA, Olsen JV and Mann M: Andromeda: A peptide search engine integrated into the MaxQuant environment. J Proteome Res. 10:1794–1805. 2011. View Article : Google Scholar : PubMed/NCBI
38	Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, Simonovic M, Roth A, Santos A, Tsafou KP, et al: STRING v10: Protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 43(Database Issue): D447–D452. 2015. View Article : Google Scholar
39	Franceschini A, Szklarczyk D, Frankild S, Kuhn M, Simonovic M, Roth A, Lin J, Minguez P, Bork P, von Mering C and Jensen LJ: STRING v9.1: Protein-protein interaction networks, with increased coverage and integration. Nucleic Acids Res. 41(Database Issue): D808–D815. 2013. View Article : Google Scholar :
40	Campbell JD, Alexandrov A, Kim J, Wala J, Berger AH, Pedamallu CS, Shukla SA, Guo G, Brooks AN, Murray BA, et al: Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas. Nat Genet. 48:607–616. 2016. View Article : Google Scholar : PubMed/NCBI
41	Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, et al: The cBio cancer genomics portal: An open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2:401–404. 2012. View Article : Google Scholar : PubMed/NCBI
42	Roesch A, Vultur A, Bogeski I, Wang H, Zimmermann KM, Speicher D, Körbel C, Laschke MW, Gimotty PA, Philipp SE, et al: Overcoming intrinsic multidrug resistance in melanoma by blocking the mitochondrial respiratory chain of slow-cycling JARID1Bhigh cells. Cancer Cell. 23:811–825. 2013. View Article : Google Scholar : PubMed/NCBI
43	Mogami T, Yokota N, Asai-Sato M, Yamada R, Koizume S, Sakuma Y, Yoshihara M, Nakamura Y, Takano Y, Hirahara F, et al: Annexin A4 is involved in proliferation, chemo-resistance and migration and invasion in ovarian clear cell adenocarcinoma cells. PLoS One. 8:e803592013. View Article : Google Scholar : PubMed/NCBI
44	Li N, Huang HQ and Zhang GS: Association between SOD2 C47T polymorphism and lung cancer susceptibility: A meta-analysis. Tumor Biol. 35:955–959. 2014. View Article : Google Scholar
45	Morales DR and Morris AD: Metformin in cancer treatment and prevention. Annu Rev Med. 66:17–29. 2015. View Article : Google Scholar
46	Guertin DA and Sabatini DM: Defining the role of mTOR in cancer. Cancer Cell. 12:9–22. 2007. View Article : Google Scholar : PubMed/NCBI
47	Sharma A, Bandyopadhayaya S, Chowdhury K, Sharma T, Maheshwari R, Das A, Chakrabarti G, Kumar V and Mandal CC: Metformin exhibited anticancer activity by lowering cellular cholesterol content in breast cancer cells. PLoS One. 14:e02094352019. View Article : Google Scholar : PubMed/NCBI
48	Lee JO, Kang MJ, Byun WS, Kim SA, Seo IH, Han JA, Moon JW, Kim JH, Kim SJ, Lee EJ, et al: Metformin overcomes resistance to cisplatin in triple-negative breast cancer (TNBC) cells by targeting RAD51. Breast Cancer Res. 21:1152019. View Article : Google Scholar : PubMed/NCBI
49	Dang JH, Jin ZJ, Liu XJ, Hu D, Wang J, Luo Y and Li LL: Metformin in combination with cisplatin inhibits cell viability and induces apoptosis of human ovarian cancer cells by inactivating ERK 1/2. Oncol Lett. 14:7557–7564. 2017.
50	Riaz MA, Sak A, Erol YB, Groneberg M, Thomale J and Stuschke M: Metformin enhances the radiosensitizing effect of cisplatin in non-small cell lung cancer cell lines with different cisplatin sensitivities. Sci Rep. 9:12822019. View Article : Google Scholar : PubMed/NCBI
51	Zhang JW, Zhao F and Sun Q: Metformin synergizes with rapamycin to inhibit the growth of pancreatic cancer in vitro and in vitro. Oncol Lett. 15:1811–1816. 2018.PubMed/NCBI
52	Jin DH, Kim Y, Lee B, Han J, Kim HK, Shim YM and Kim DH: Metformin induces cell cycle arrest at the G1 phase through E2F8 suppression in lung cancer cells. Oncotarget. 8:101509–101519. 2017. View Article : Google Scholar : PubMed/NCBI
53	Queiroz EAIF, Puukila S, Eichler R, Sampaio SC, Forsyth HL, Lees SJ, Barbosa AM, Dekker RF, Fortes ZB and Khaper N: Metformin induces apoptosis and cell cycle arrest mediated by oxidative stress, AMPK and FOXO3a in MCF-7 breast cancer cells. PLoS One. 9. pp. e982072014, View Article : Google Scholar
54	Xie W, Wang L, Sheng H, Qiu J, Zhang D, Zhang L, Yang F, Tang D and Zhang K: Metformin induces growth inhibition and cell cycle arrest by upregulating MicroRNA34a in renal cancer cells. Med Sci Monit. 23:29–37. 2017. View Article : Google Scholar : PubMed/NCBI
55	Lundholm L, Hååg P, Zong D, Juntti T, Mörk B, Lewensohn R and Viktorsson K: Resistance to DNA-damaging treatment in non-small cell lung cancer tumor-initiating cells involves reduced DNA-PK/ATM activation and diminished cell cycle arrest. Cell Death Dis. 4:e4782013. View Article : Google Scholar : PubMed/NCBI
56	Chatterjee A, Mukhopadhyay S, Tung K, Patel D and Foster DA: Rapamycin-induced G1 cell cycle arrest employs both TGF-β and Rb pathways. Cancer Lett. 360:134–140. 2015. View Article : Google Scholar : PubMed/NCBI
57	Lu Z, Peng K, Wang N, Liu HM and Hou G: Downregulation of p70S6K enhances cell sensitivity to rapamycin in esophageal squamous cell carcinoma. J Immunol Res. 2016:78289162016. View Article : Google Scholar : PubMed/NCBI
58	Song J, Wang X, Zhu J and Liu J: Rapamycin causes growth arrest and inhibition of invasion in human chondrosarcoma cells. J BUON. 21:244–251. 2016.PubMed/NCBI
59	Wang Y, Xu W, Yan Z, Zhao W, Mi J, Li J and Yan H: Metformin induces autophagy and G0/G1 phase cell cycle arrest in myeloma by targeting the AMPK/mTORC1 and mTORC2 pathways. J Exp Clin Cancer Res. 37:632018. View Article : Google Scholar : PubMed/NCBI
60	Zhong DS, Sun LL and Dong LX: Molecular mechanisms of LKB1 induced cell cycle arrest. Thorac Cancer. 4:229–233. 2013. View Article : Google Scholar : PubMed/NCBI
61	Zhang Y, Bao C, Mu Q, Chen J, Wang J, Mi Y, Sayari AJ, Chen Y and Guo M: Reversal of cisplatin resistance by inhibiting PI3K/Akt signal pathway in human lung cancer cells. Neoplasma. 63:362–370. 2016. View Article : Google Scholar
62	Sheng J, Shen L, Sun L, Zhang X, Cui R and Wang L: Inhibition of PI3K/mTOR increased the sensitivity of hepatocellular carcinoma cells to cisplatin via interference with mitochondrial-lysosomal crosstalk. Cell Prolif. 52:e126092019. View Article : Google Scholar : PubMed/NCBI
63	Hou G, Yang S, Zhou Y, Wang C, Zhao W and Lu Z: Targeted inhibition of mTOR signaling improves sensitivity of esophageal squamous cell carcinoma cells to cisplatin. J Immunol Res. 2014:8457632014. View Article : Google Scholar : PubMed/NCBI
64	Zhao Y, Sun H, Feng M, Zhao J, Zhao X, Wan Q and Cai D: Metformin is associated with reduced cell proliferation in human endometrial cancer by inbibiting PI3K/AKT/mTOR signaling. Gynecol Endocrinol. 34:428–432. 2018. View Article : Google Scholar
65	Galluzzi L, Senovilla L, Vitale I, Michels J, Martins I, Kepp O, Castedo M and Kroemer G: Molecular mechanisms of cisplatin resistance. Oncogene. 31:1869–1883. 2012. View Article : Google Scholar
66	Galluzzi L, Vitale I, Michels J, Brenner C, Szabadkai G, Harel-Bellan A, Castedo M and Kroemer G: Systems biology of cisplatin resistance: Past, present and future. Cell Death Dis. 5:e12572014. View Article : Google Scholar : PubMed/NCBI
67	Pandey A and Mann M: Proteomics to study genes and genomes. Nature. 405:837–846. 2000. View Article : Google Scholar : PubMed/NCBI
68	Chang X, Ravi R, Pham V, Bedi A, Chatterjee A and Sidransky D: Adenylate kinase 3 sensitizes cells to cigarette smoke condensate vapor induced cisplatin resistance. PLoS One. 6:e208062011. View Article : Google Scholar : PubMed/NCBI
69	Wei Y, Wu S, Xu W, Liang Y, Li Y, Zhao W and Wu J: Depleted aldehyde dehydrogenase 1A1 (ALDH1A1) reverses cisplatin resistance of human lung adenocarcinoma cell A549/DDP. Thorac Cancer. 8:26–32. 2017. View Article : Google Scholar :
70	Morimoto A, Serada S, Enomoto T, Kim A, Matsuzaki S, Takahashi T, Ueda Y, Yoshino K, Fujita M, Fujimoto M, et al: Annexin A4 induces platinum resistance in a chloride-and calcium-dependent manner. Oncotarget. 5:7776–7787. 2014. View Article : Google Scholar : PubMed/NCBI
71	Feng X, Liu H, Zhang Z, Gu Y, Qiu H and He Z: Annexin A2 contributes to cisplatin resistance by activation of JNK-p53 pathway in non-small cell lung cancer cells. J Exp Clin Cancer Res. 36:1232017. View Article : Google Scholar : PubMed/NCBI
72	Becker M, De Bastiani MA, Müller CB, Markoski MM, Castro MA and Klamt F: High cofilin-1 levels correlate with cisplatin resistance in lung adenocarcinomas. Tumor Biology. 35:1233–1238. 2014. View Article : Google Scholar
73	Wittig R, Nessling M, Will RD, Mollenhauer J, Salowsky R, Münstermann E, Schick M, Helmbach H, Gschwendt B, Korn B, et al: Candidate genes for cross-resistance against DNA-damaging drugs. Cancer Res. 62:6698–6705. 2002.PubMed/NCBI
74	Zeller C, Dai W, Steele NL, Siddiq A, Walley AJ, Wilhelm-Benartzi CS, Rizzo S, van der Zee A, Plumb JA and Brown R: Candidate DNA methylation drivers of acquired cisplatin resistance in ovarian cancer identified by methylome and expression profiling. Oncogene. 31:4567–4576. 2012. View Article : Google Scholar : PubMed/NCBI
75	Yang M, Li Y, Shen X, Ruan Y, Lu Y, Jin X, Song P, Guo Y, Zhang X, Qu H, et al: CLDN6 promotes chemoresistance through GSTP1 in human breast cancer. J Exp Clin Cancer Res. 36:1572017. View Article : Google Scholar : PubMed/NCBI
76	Zhang R, Tao F, Ruan S, Hu M, Hu Y, Fang Z, Mei L and Gong C: The TGFβ1-FOXM1-HMGA1-TGFβ1 positive feedback loop increases the cisplatin resistance of non-small cell lung cancer by inducing G6PD expression. Am J Transl Res. 11:6860–6876. 2019.
77	Wang JM, Liu BQ, Zhang Q, Hao L, Li C, Yan J, Zhao FY, Qiao HY, Jiang JY and Wang HQ: ISG15 suppresses translation of ABCC2 via ISGylation of hnRNPA2B1 and enhances drug sensitivity in cisplatin resistant ovarian cancer cells. Biochim Biophys Acta Mol Cell Res. 1867:1186472020. View Article : Google Scholar : PubMed/NCBI
78	Di Martino S, Amoreo CA, Nuvoli B, Galati R, Strano S, Facciolo F, Alessandrini G, Pass HI, Ciliberto G, Blandino G, et al: HSP90 inhibition alters the chemotherapy-driven rearrangement of the oncogenic secretome. Oncogene. 37:1369–1385. 2018. View Article : Google Scholar : PubMed/NCBI
79	Qin X, Sun L and Wang J: Restoration of microRNA-708 sensitizes ovarian cancer cells to cisplatin via IGF2BP1/Akt pathway. Cell Biol Int. 41:1110–1118. 2017. View Article : Google Scholar : PubMed/NCBI
80	Xu Z, Zou L, Ma G, Wu X, Huang F, Feng T, Li S, Lin Q, He X, Liu Z and Cao X: Integrin β1 is a critical effector in promoting metastasis and chemo-resistance of esophageal squamous cell carcinoma. Am J Cancer Res. 7:531–542. 2017.
81	Li Y, Liu X, Lin X, Zhao M, Xiao Y, Liu C, Liang Z, Lin Z, Yi R, Tang Z, et al: Chemical compound cinobufotalin potently induces FOXO1-stimulated cisplatin sensitivity by antagonizing its binding partner MYH9. Signal Transduct Target Ther. 4:482019. View Article : Google Scholar : PubMed/NCBI
82	Depeng S, Wu J, Guo L, Xu Y, Liu L and Lu J: Metformin increases sensitivity of osteosarcoma stem cells to cisplatin by inhibiting expression of PKM2. Int J Oncol. 50:1848–1856. 2017. View Article : Google Scholar
83	Zhu H, Wu J, Zhang W, Luo H, Shen Z, Cheng H and Zhu X: PKM2 enhances chemosensitivity to cisplatin through interaction with the mTOR pathway in cervical cancer. Sci Rep. 6:307882016. View Article : Google Scholar : PubMed/NCBI
84	Wang Y, Hao F, Nan Y, Qu L, Na W, Jia C and Chen X: PKM2 inhibitor shikonin overcomes the cisplatin resistance in bladder cancer by inducing necroptosis. International J Biol Sci. 14:1883–1891. 2018. View Article : Google Scholar
85	Krafft U, Tschirdewahn S, Hess J, Harke NN, Hadaschik BA, Nyirády P, Szendröi A, Szücs M, Módos O, Olah C, et al: STIP1 tissue expression is associated with survival in chemotherapy-treated bladder cancer patients. Pathol Oncol Res. 26:1243–1249. 2020. View Article : Google Scholar
86	Li C, Cai J, Ge F and Wang G: TGM2 knockdown reverses cisplatin chemoresistance in osteosarcoma. Int J Molr Med. 42:1799–1808. 2018.
87	Yang H, Wu XL, Wu KH, Zhang R, Ju LL, Ji Y, Zhang YW, Xue SL, Zhang YX, Yang YF and Yu MM: MicroRNA-497 regulates cisplatin chemosensitivity of cervical cancer by targeting transketolase. Am J Cancer Res. 6:2690–2699. 2016.PubMed/NCBI
88	Matassa DS, Amoroso MR, Lu H, Avolio R, Arzeni D, Procaccini C, Faicchia D, Maddalena F, Simeon V, Agliarulo I, et al: Oxidative metabolism drives inflammation-induced platinum resistance in human ovarian cancer. Cell Death Differ. 23:1542–1554. 2016. View Article : Google Scholar : PubMed/NCBI
89	Yue T, Zheng X, Dou Y, Zheng X, Sun R, Tian Z and Wei H: Interleukin 12 shows a better curative effect on lung cancer than paclitaxel and cisplatin doublet chemotherapy. BMC Cancer. 16:6652016. View Article : Google Scholar : PubMed/NCBI
90	Barros FBA, Assao A, Garcia NG, Nonogaki S, Carvalho AL, Soares FA, Kowalski LP and Oliveira DT: Moesin expression by tumor cells is an unfavorable prognostic biomarker for oral cancer. BMC Cancer. 18:532018. View Article : Google Scholar : PubMed/NCBI
91	Alam F, Mezhal F, El Hasasna H, Nair VA, Aravind SR, Saber Ayad M, El-Serafi A and Abdel-Rahman WM: The role of p53-microRNA 200-Moesin axis in invasion and drug resistance of breast cancer cells. Tumor Bio. 39:10104283177146342017.
92	Wang Q, Lu X, Zhao S, Pang M, Wu X, Wu H, Hoffman RM, Yang Z and Zhang Y: Moesin expression is associated with glioblastoma cell proliferation and invasion. Anticancer Res. 37:2211–2218. 2017. View Article : Google Scholar : PubMed/NCBI
93	Wang J, Gao Q, Wang D, Wang Z and Hu C: Metformin inhibits growth of lung adenocarcinoma cells by inducing apoptosis via the mitochondria-mediated pathway. Oncol Lett. 10:1343–1349. 2015. View Article : Google Scholar : PubMed/NCBI
94	Seguin L, Desgrosellier JS, Weis SM and Cheresh DA: Integrins and cancer: Regulators of cancer stemness, metastasis, and drug resistance. Trends Cell Biol. 25:234–240. 2015. View Article : Google Scholar : PubMed/NCBI
95	Blandin AF, Renner G, Lehmann M, Lelong-Rebel I, Martin S and Dontenwill M: β1 integrins as therapeutic targets to disrupt hallmarks of cancer. Front Pharmacol. 6:2792015. View Article : Google Scholar
96	Ju L, Zhou C, Li W and Yan L: Integrin beta1 over-expression associates with resistance to tyrosine kinase inhibitor gefitinib in non-small cell lung cancer. J Cel Biochem. 111:1565–1574. 2010. View Article : Google Scholar
97	Kanda R, Kawahara A, Watari K, Murakami Y, Sonoda K, Maeda M, Fujita H, Kage M, Uramoto H, Costa C, et al: Erlotinib resistance in lung cancer cells mediated by integrin β1/Src/Akt-driven bypass signaling. Cancer Res. 73:6243–6253. 2013. View Article : Google Scholar : PubMed/NCBI
98	Gachechiladze M, Skarda J, Janikova M, Mgebrishvili G, Kharaishvili G, Kolek V, Grygarkova I, Klein J, Poprachova A, Arabuli M and Kolar Z: Overexpression of filamin-A protein is associated with aggressive phenotype and poor survival outcomes in NSCLC patients treated with platinum-based combination chemotherapy. Neoplasma. 63:274–281. 2016.PubMed/NCBI
99	Ji ZM, Yang LL, Ni J, Xu SP, Yang C, Duan P, Lou LP and Ruan QR: Silencing filamin a inhibits the invasion and migration of breast cancer cells by up-regulating 14-3-3σ. Curr Med Sci. 38:461–466. 2018. View Article : Google Scholar : PubMed/NCBI
100	Li L, Lu Y, Stemmer PM and Chen F: Filamin A phosphorylation by Akt promotes cell migration in response to arsenic. Oncotarget. 6:12009–12019. 2015. View Article : Google Scholar : PubMed/NCBI
101	Guo Y, Li M, Bai G, Li X, Sun Z, Yang J, Wang L and Sun J: Filamin a inhibits tumor progression through regulating BRCA1 expression in human breast cancer. Oncol Lett. 16:6261–6266. 2018.PubMed/NCBI
102	Donadon M, Di Tommaso L, Soldani C, Franceschini B, Terrone A, Mimmo A, Vitali E, Roncalli M, Lania A and Torzilli G: Filamin A expression predicts early recurrence of hepatocellular carcinoma after hepatectomy. Liver Int. 38:303–311. 2018. View Article : Google Scholar
103	Maynadier M, Farnoud R, Lamy PJ, Laurent-Matha V, Garcia M and Rochefort H: Cathepsin D stimulates the activities of secreted plasminogen activators in the breast cancer acidic environment. Int J Oncol. 43:1683–1690. 2013. View Article : Google Scholar : PubMed/NCBI
104	Hah YS, Noh HS, Ha JH, Ahn JS, Hahm JR, Cho HY and Kim DR: Cathepsin D inhibits oxidative stress-induced cell death via activation of autophagy in cancer cells. Cancer Lett. 323:208–214. 2012. View Article : Google Scholar : PubMed/NCBI
105	Zhang C, Zhang M and Song S: Cathepsin D enhances breast cancer invasion and metastasis through promoting hepsin ubiquitin-proteasome degradation. Cancer Lett. 438:105–115. 2018. View Article : Google Scholar : PubMed/NCBI
106	Kang SW: Superoxide dismutase 2 gene and cancer risk: Evidence from an updated meta-analysis. Int J Clin Exp Med. 8:14647–14655. 2015.PubMed/NCBI
107	Lee JH, Choi IY, Kil IS, Kim SY, Yang ES and Park JW: Protective role of superoxide dismutases against ionizing radiation in yeast. Biochim Biophys Acta. 1526:191–198. 2001. View Article : Google Scholar : PubMed/NCBI
108	Epperly MW, Gretton JE, Sikora CA, Jefferson M, Bernarding M, Nie S and Greenberger JS: Mitochondrial localization of superoxide dismutase is required for decreasing radiation-induced cellular damage. Radiat Res. 160:568–578. 2003. View Article : Google Scholar : PubMed/NCBI
109	Takada Y, Hachiya M, Park SH, Osawa Y, Ozawa T and Akashi M: Role of reactive oxygen species in cells overexpressing manganese superoxide dismutase: Mechanism for induction of radioresistance. Mol Cancer Res. 1:137–146. 2002.PubMed/NCBI
110	Hosoki A, Yonekura S, Zhao QL, Wei ZL, Takasaki I, Tabuchi Y, Wang LL, Hasuike S, Nomura T, Tachibana A, et al: Mitochondria-targeted superoxide dismutase (SOD2) regulates radiation resistance and radiation stress response in HeLa cells. J Radiat Res. 53:58–71. 2012. View Article : Google Scholar : PubMed/NCBI
111	Cruz-Bermúdez A, Laza-Briviesca R, Vicente-Blanco RJ, García-Grande A, Coronado MJ, Laine-Menéndez S, Palacios-Zambrano S, Moreno-Villa MR, Ruiz-Valdepeñas AM, Lendinez C, et al: Cisplatin resistance involves a metabolic reprogramming through ROS and PGC-1α in NSCLC which can be overcome by OXPHOS inhibition. Free Radic Biol Med. 135:167–181. 2019. View Article : Google Scholar
112	Zuo J, Zhao M, Liu B, Han X, Li Y, Wang W, Zhang Q, Lv P, Xing L, Shen H and Zhang X: TNF-α-mediated upregulation of SOD-2 contributes to cell proliferation and cisplatin resistance in esophageal squamous cell carcinoma. Oncol Rep. 42:1497–1506. 2019.PubMed/NCBI
113	Yan X, Pan L, Yuan Y, Lang JH and Mao N: Identification of platinum-resistance associated proteins through proteomic analysis of human ovarian cancer cells and their platinum-resistant sublines. J Proteome Res. 6:772–780. 2007. View Article : Google Scholar : PubMed/NCBI
114	Matsuzaki S, Enomoto T, Serada S, Yoshino K, Nagamori S, Morimoto A, Yokoyama T, Kim A, Kimura T, Ueda Y, et al: Annexin A4-conferred platinum resistance is mediated by the copper transporter ATP7A. Int J Cancer. 134:1796–1809. 2014. View Article : Google Scholar
115	Yao HS, Sun C, Li XX, Wang Y, Jin KZ, Zhang XP and Hu ZQ: Annexin A4-nuclear factor-κB feedback circuit regulates cell malignant behavior and tumor growth in gallbladder cancer. Sci Rep. 6:310562016. View Article : Google Scholar
116	Yamashita T, Nagano K, Kanasaki S, Maeda Y, Furuya T, Inoue M, Nabeshi H, Yoshikawa T, Yoshioka Y, Itoh N, et al: Annexin A4 is a possible biomarker for cisplatin susceptibility of malignant mesothelioma cells. Biochem Biophys Res Commun. 421:140–144. 2012. View Article : Google Scholar : PubMed/NCBI
117	Vizcaíno JA, Deutsch EW, Wang R, Csordas A, Reisinger F, Ríos D, Dianes JA, Sun Z, Farrah T, Bandeira N, et al: ProteomeXchange provides globally coordinated proteomics data submission and dissemination. Nat Biotechnol. 32:223–226. 2014. View Article : Google Scholar : PubMed/NCBI