Metformin sensitizes EGFR-TKI-Resistant human lung cancer cells in vitro and in vivo through inhibition of IL-6 signaling and EMT reversal

Clinical Cancer Research

Volumn 20, Issue 10, 2014, Pages 2714-2726

  Li, Li ^a,b   Han, Rui ^c   Xiao, Hualiang ^a   Lin, Caiyu ^a   Wang, Yubo ^a   Liu, Hao ^a   Li, Kunlin ^a   Chen, Hengyi ^a   Sun, Fenfen ^a   Yang, Zhenzhou ^d   Jiang, Jianxin ^e   He, Yong ^a  

^a THIRD MILITARY MEDICAL UNIVERSITY   (China)

^b Departments of Thoracic Surgery   (China)

^c Departments of Pathology   (China)

^d Departments of Oncology   (China)

^e THIRD MILITARY MEDICAL UNIVERSITY   (China)

Author keywords

[No Author keywords available]

Indexed keywords

EPIDERMAL GROWTH FACTOR RECEPTOR KINASE INHIBITOR; ERLOTINIB; GEFITINIB; INTERLEUKIN 6; METFORMIN; STAT3 PROTEIN; ANTINEOPLASTIC AGENT; EPIDERMAL GROWTH FACTOR RECEPTOR; PROTEIN KINASE INHIBITOR; QUINAZOLINE DERIVATIVE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; BRDU ASSAY; CANCER INHIBITION; CANCER RESISTANCE; CELL INVASION; CELL INVASION ASSAY; CELL MIGRATION; CELL PROLIFERATION; CONTROLLED STUDY; CYTOKINE RELEASE; DRUG ACTIVITY; DRUG EFFICACY; DRUG POTENTIATION; DRUG SENSITIZATION; EPITHELIAL MESENCHYMAL TRANSITION; FEMALE; FLOW CYTOMETRY; IMMUNOHISTOCHEMISTRY; IN VITRO STUDY; IN VIVO STUDY; LUNG CANCER CELL LINE; MONOTHERAPY; MOUSE; MTT ASSAY; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN SECRETION; SIGNAL TRANSDUCTION; TUMOR XENOGRAFT; WESTERN BLOTTING; ANIMAL; ANTAGONISTS AND INHIBITORS; BAGG ALBINO MOUSE; CELL MOTION; CELL SURVIVAL; DRUG EFFECTS; DRUG RESISTANCE; DRUG SCREENING; GENETICS; HUMAN; KAPLAN MEIER METHOD; LUNG NEOPLASMS; METABOLISM; NUDE MOUSE; PATHOLOGY; TUMOR CELL LINE;

ANIMALS; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; BLOTTING, WESTERN; CELL LINE, TUMOR; CELL MOVEMENT; CELL SURVIVAL; DRUG RESISTANCE, NEOPLASM; DRUG SYNERGISM; EPITHELIAL-MESENCHYMAL TRANSITION; FEMALE; FLOW CYTOMETRY; HUMANS; IMMUNOHISTOCHEMISTRY; INTERLEUKIN-6; KAPLAN-MEIER ESTIMATE; LUNG NEOPLASMS; METFORMIN; MICE; MICE, INBRED BALB C; MICE, NUDE; PROTEIN KINASE INHIBITORS; QUINAZOLINES; RECEPTOR, EPIDERMAL GROWTH FACTOR; SIGNAL TRANSDUCTION; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 84901036169     PISSN: 10780432     EISSN: 15573265     Source Type: Journal    
DOI: 10.1158/1078-0432.CCR-13-2613     Document Type: Article

References (50)

1. Soria JC, Mok TS, Cappuzzo F, Janne PA. EGFR-mutated oncogeneaddicted non-small cell lung cancer: current trends and future prospects. Cancer Treat Rev 2012;38:416-30.
2. Nguyen KS, Neal JW. First-line treatment of EGFR-mutant non-smallcell lung cancer: the role of erlotinib and other tyrosine kinase inhibitors. Biologics 2012;6:337-45.
3. Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2005;2:e73.
4. Engelman JA, Janne PA. Mechanisms of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in nonsmall cell lung cancer. Clin Cancer Res 2008;14:2895-9.
5. Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell 2009;139:871-90.
6. Voulgari A, Pintzas A. Epithelial-mesenchymal transition in cancer metastasis: mechanisms, markers and strategies to overcome drug resistance in the clinic. Biochim Biophys Acta 2009;1796:75-90.
7. Neel DS, Bivona TG. Secrets of drug resistance in NSCLC exposed by new molecular definition of EMT. Clin Cancer Res 2013;19:3-5.
8. Uramoto H, Iwata T, Onitsuka T, Shimokawa H, Hanagiri T, Oyama T. Epithelial-mesenchymal transition in EGFR-TKI acquired resistant lung adenocarcinoma. Anticancer Res 2010;30:2513-7.
9. Bruzzese F, Leone A, Rocco M, Carbone C, Piro G, Caraglia M, et al. HDAC inhibitor vorinostat enhances the antitumor effect of gefitinib in squamous cell carcinoma of head and neck by modulating ErbB receptor expression and reverting EMT. J Cell Physiol 2011;226: 2378-90.
10. Yao Z, Fenoglio S, Gao DC, Camiolo M, Stiles B, Lindsted T, et al. TGFb IL-6 axis mediates selective and adaptive mechanisms of resistance to molecular targeted therapy in lung cancer. Proc Natl Acad Sci U S A 2010;107:15535-40.
11. Kim SM,Kwon OJ, Hong YK, Kim JH, Solca F, Ha SJ, et al. Activation of IL-6R/JAK1/STAT3 signaling induces De Novo resistance to irreversible EGFR inhibitors in non-small cell lung cancer with T790M resistance mutation. Mol Cancer Ther 2012;11:2254-64.
12. Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. BMJ 2005;330:1304-5.
13. Hirsch HA, Iliopoulos D, Struhl K. Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth. Proc Natl Acad Sci U S A 2013;110:972-7.
14. Iliopoulos D, Hirsch HA, Struhl K. Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types. Cancer Res 2011;71:3196-201.
15. Cufi S, Vazquez-Martin A, Oliveras-Ferraros C, Martin-Castillo B, Joven J, Menendez JA. Metformin against TGF-b-induced epithelial- to-mesenchymal transition (EMT): from cancer stem cells to agingassociated fibrosis. Cell Cycle 2010;9:4461-8.
16. Lin CC, Yeh HH, Huang WL, Yan JJ, Lai WW, Su WP, et al. Metformin enhances cisplatin cytotoxicity by suppressing stat3 activity independently of the LKB1-AMPK pathway. Am J Respir Cell Mol Biol 2013;49:241-50.
17. Morgillo F, Sasso FC, Della Corte CM, Vitagliano D, D'Aiuto E, Troiani T, et al. Synergistic effects of metformin treatment in combination with gefitinib, a selective EGFR tyrosine kinase inhibitor, in LKB1 wild-type NSCLC cell lines. Clin Cancer Res 2013;19:3508-19.
18. Xu X, Fan Z, Kang L, Han J, Jiang C, Zheng X, et al. Hepatitis B virus X protein represses miRNA-148a to enhance tumorigenesis. J Clin Invest 2013;123:630-45.
19. Li L, Hartley R, Reiss B, Sun Y, Pu J, Wu D, et al. E-cadherin plays an essential role in collective directional migration of large epithelial sheets. Cell Mol Life Sci 2012;69:2779-89.
20. Chung JH, Rho JK, Xu X, Lee JS, Yoon HI, Lee CT, et al. Clinical and molecular evidences of epithelial to mesenchymal transition in acquired resistance to EGFR-TKIs. Lung Cancer 2011;73:176-82.
21. Ruiter R, Visser LE, van Herk-Sukel MP, Coebergh JW, Haak HR, Geelhoed-Duijvestijn PH, et al. Lower risk of cancer in patients on metformin in comparison with those on sulfonylurea derivatives: results from a large population-based follow-up study. Diabetes Care 2012;35:119-24.
22. Chaiteerakij R, Yang JD, Harmsen WS, Slettedahl SW, Mettler TA, Fredericksen ZS, et al. Risk factors for intrahepatic cholangiocarcinoma: association between metformin use and reduced cancer risk. Hepatology 2013;57:648-55.
23. Zhang ZJ, Zheng ZJ, Kan H, Song Y, Cui W, Zhao G, et al. Reduced risk of colorectal cancer with metformin therapy in patients with type 2 diabetes: a meta-Analysis. Diabetes Care 2011;34:2323-8.
24. Jiralerspong S, Palla SL, Giordano SH, Meric-Bernstam F, Liedtke C, Barnett CM, et al. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol 2009;27:3297-302.
25. Salani B, Maffioli S, Hamoudane M, Parodi A, Ravera S, Passalacqua M, et al. Caveolin-1 is essential for metformin inhibitory effect on IGF1 action in non-small-cell lung cancer cells. FASEB J 2012;26:788-98.
26. Zakikhani M, Dowling R, Fantus IG, Sonenberg N, Pollak M. Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res 2006;66:10269-73.
27. Hirsch HA, Iliopoulos D, Tsichlis PN, Struhl K. Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res 2009;69: 7507-11.
28. Hirsch HA, Iliopoulos D, Joshi A, Zhang Y, Jaeger SA, Bulyk M, et al. A transcriptional signature and common gene networks link cancer with lipid metabolism and diverse human diseases. Cancer Cell 2010; 17:348-61.
29. Reagan-Shaw S, Nihal M, Ahmad N. Dose translation from animal to human studies revisited. FASEB J 2008;22:659-61.
30. Chiu HC, Chou DL, Huang CT, Lin WH, Lien TW, Yen KJ, et al. Suppression of Stat3 activity sensitizes gefitinib-resistant non small cell lung cancer cells. Biochem Pharmacol 2011;81:1263-70.
31. Schafer ZT, Brugge JS. IL-6 involvement in epithelial cancers. J Clin Invest 2007;117:3660-3.
32. Zhang Z, Lee JC, Lin L, Olivas V, Au V, LaFramboise T, et al. Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nat Genet 2012;44:852-60.
33. Sullivan NJ, Sasser AK, Axel AE, Vesuna F, Raman V, Ramirez N, et al. Interleukin-6 induces an epithelial-mesenchymal transition phenotype in human breast cancer cells. Oncogene 2009;28:2940-7.
34. Al-Ejeh F, Smart CE, Morrison BJ, Chenevix-Trench G, Lopez JA, Lakhani SR, et al. Breast cancer stem cells: treatment resistance and therapeutic opportunities. Carcinogenesis 2011;32:650-8.
35. Ho MM, Ng AV, Lam S, Hung JY. Side population in human lung cancer cell lines and tumors is enriched with stem-like cancer cells. Cancer Res 2007;67:4827-33.
36. Eramo A, Lotti F, Sette G, Pilozzi E, Biffoni M, Di Virgilio A, et al. Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ 2008;15:504-14.
37. Levina V, Marrangoni AM, DeMarco R, Gorelik E, Lokshin AE. Drugselected human lung cancer stem cells: cytokine network, tumorigenic and metastatic properties. PLoS ONE 2008;3:e3077.
38. Shien K, Toyooka S, Yamamoto H, Soh J, Jida M, Thu KL, et al. Acquired resistance to EGFR inhibitors is associated with a manifestation of stem cell-like properties in cancer cells. Cancer Res 2013; 73:3051-61.
39. Yadav A, Kumar B, Datta J, Teknos TN, Kumar P. IL-6 promotes head and neck tumor metastasis by inducing epithelial-mesenchymal transition via the JAK-STAT3-SNAIL signaling pathway. Mol Cancer Res 2011;9:1658-67.
40. Xie G, Yao Q, Liu Y, Du S, Liu A, Guo Z, et al. IL-6-induced epithelialmesenchymal transition promotes the generation of breast cancer stem-like cells analogous to mammosphere cultures. Int J Oncol 2012;40:1171-9.
41. Singh A, Settleman J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 2010;29: 4741-51.
42. Oliveras-Ferraros C, Vazquez-Martin A, Martin-Castillo B, Perez-Martinez MC, Cufi S, Del Barco S, et al. Pathway-focused proteomic signatures in HER2-overexpressing breast cancer with a basal-like phenotype: new insights into de novo resistance to trastuzumab (Herceptin). Int J Oncol 2010;37:669-78.
43. Shank JJ, Yang K, Ghannam J, Cabrera L, Johnston CJ, Reynolds RK, et al. Metformin targets ovarian cancer stem cells in vitro and in vivo. Gynecol Oncol 2012;127:390-7.
44. Bao B, Wang Z, Ali S, Ahmad A, Azmi AS, Sarkar SH, et al. Metformin inhibits cell proliferation, migration and invasion by attenuating CSC function mediated by deregulating miRNAs in pancreatic cancer cells. Cancer Prev Res 2012;5:355-64.
45. Chen G, Xu S, Renko K, Derwahl M. Metformin inhibits growth of thyroid carcinoma cells, suppresses self-renewal of derived cancer stem cells, and potentiates the effect of chemotherapeutic agents. J Clin Endocrinol Metab 2012;97:E510-20.
46. Vazquez-Martin A, Oliveras-Ferraros C, Cufi S, Del Barco S, Martin- Castillo B, Menendez JA. Metformin regulates breast cancer stem cell ontogeny by transcriptional regulation of the epithelial-mesenchymal transition (EMT) status. Cell Cycle 2010;9:3807-14.
47. InoueA, Saijo Y,Maemondo M,Gomi K, Tokue Y,Kimura Y, et al. Severe acute interstitial pneumonia and gefitinib. Lancet 2003;361:137-9.
48. Moodley YP, Misso NL, Scaffidi AK, Fogel-Petrovic M, McAnulty RJ, Laurent GJ, et al. Inverse effects of interleukin-6 on apoptosis of fibroblasts from pulmonary fibrosis and normal lungs. Am J Respir Cell Mol Biol 2003;29:490-8.
49. Ishiguro Y, Ishiguro H, Miyamoto H. Epidermal growth factor receptor tyrosine kinase inhibition up-regulates interleukin-6 in cancer cells and induces subsequent development of interstitial pneumonia. Oncotarget 2013;4:550-9.
50. Zhou Y, Lee JY, Lee CM, Cho WK, Kang MJ, Koff JL, et al. Amphiregulin, an epidermal growth factor receptor ligand, plays an essential role in the pathogenesis of transforming growth factor-beta-induced pulmonary fibrosis. J Biol Chem 2012;287:41991-2000.