Metformin increases antitumor activity of MEK inhibitors through GLI1 downregulation in LKB1 positive human NSCLC cancer cells

Oncotarget

Volumn 7, Issue 4, 2016, Pages 4265-4278

  Della Corte, Carminia Maria ^a   Ciaramella, Vincenza ^a   Di Mauro, Concetta ^b   Castellone, Maria Domenica ^b   Papaccio, Federica ^a   Fasano, Morena ^a   Sasso, Ferdinando Carlo ^a   Martinelli, Erika ^a   Troiani, Teresa ^a   De Vita, Ferdinando ^a   Orditura, Michele ^a   Bianco, Roberto ^b   Ciardiello, Fortunato ^a   Morgillo, Floriana ^a  

^a SECOND UNIVERSITY OF NAPLES   (Italy)

^b UNIVERSITY OF NAPLES FEDERICO II   (Italy)

Author keywords

MEK; Metformin; NSCLC; Pimasertib; Selumetinib

Indexed keywords

METFORMIN; PIMASERTIB; PROTEIN KINASE LKB1; SELUMETINIB; TRANSCRIPTION FACTOR GLI1; ANTIDIABETIC AGENT; ANTINEOPLASTIC AGENT; BENZIMIDAZOLE DERIVATIVE; GLI1 PROTEIN, HUMAN; MITOGEN ACTIVATED PROTEIN KINASE KINASE 1; N-(2,3-DIHYDROXYPROPYL)-1-((2-FLUORO-4-IODOPHENYL)AMINO)ISONICOTINAMIDE; NICOTINAMIDE; PROTEIN KINASE INHIBITOR; PROTEIN SERINE THREONINE KINASE; STK11 PROTEIN, HUMAN; TRANSCRIPTION FACTOR;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CELL INVASION; CELL MIGRATION; CELL PROLIFERATION; CONCENTRATION RESPONSE; CONTROLLED STUDY; DOWN REGULATION; DRUG POTENTIATION; FEMALE; HUMAN; HUMAN CELL; IN VITRO STUDY; IN VIVO STUDY; MOUSE; NON SMALL CELL LUNG CANCER; NONHUMAN; ANALOGS AND DERIVATIVES; ANIMAL; ANTAGONISTS AND INHIBITORS; APOPTOSIS; BAGG ALBINO MOUSE; CARCINOMA, NON-SMALL-CELL LUNG; CHROMATIN IMMUNOPRECIPITATION; DRUG EFFECTS; DRUG SCREENING; ENZYME IMMUNOASSAY; GENE EXPRESSION REGULATION; LUNG NEOPLASMS; METABOLISM; NUDE MOUSE; PATHOLOGY; SECONDARY; TUMOR CELL CULTURE; WESTERN BLOTTING;

ANIMALS; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; APOPTOSIS; BENZIMIDAZOLES; BLOTTING, WESTERN; CARCINOMA, NON-SMALL-CELL LUNG; CELL PROLIFERATION; CHROMATIN IMMUNOPRECIPITATION; DRUG SYNERGISM; FEMALE; GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS; HYPOGLYCEMIC AGENTS; IMMUNOENZYME TECHNIQUES; LUNG NEOPLASMS; MAP KINASE KINASE 1; METFORMIN; MICE; MICE, INBRED BALB C; MICE, NUDE; NIACINAMIDE; PROTEIN KINASE INHIBITORS; PROTEIN-SERINE-THREONINE KINASES; TRANSCRIPTION FACTORS; TUMOR CELLS, CULTURED; XENOGRAFT MODEL ANTITUMOR ASSAYS; ZINC FINGER PROTEIN GLI1;

EID: 84958019588     PISSN: None     EISSN: 19492553     Source Type: Journal    
DOI: 10.18632/oncotarget.6559     Document Type: Article

References (42)

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015; 65: 5-29.
2. Besse B, Adjei A, Baas P, Meldgaard P, Nicolson M, Paz-Ares L et al. 2nd ESMO Consensus Conference on Lung Cancer: non-small-cell lung cancer first-line/second and further lines of treatment in advanced disease. Ann Oncol 2014; 9: 1-10.
3. 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.
4. Gotlieb WH, Saumet J, Beauchamp MC, Gu J, Lau S, Pollak MN, et al. In vitrometformin antineoplastic activity in epithelial ovarian cancer. Gynecol Oncol 2008;110:246-50.
5. Alimova IN, Liu B, Fan Z, Edgerton SM, Dillon T, Lind SE, et al. Metformin inhibits breast cancer cell growth, colony formation and induces cell cycle arrest in vitro. Cell Cycle 2009;8: 909-15.
6. Liu B, Fan Z, Edgerton SM, Deng XS, Alimova IN, Lind SE, et al. Metformin induces unique biological and molecular responses in triple negative breast cancer cells. Cell Cycle 2009;8: 2031-40. 9.
7. Wang LW, Li ZS, Zou DW, Jin ZD, Gao J, Xu GM. Metformin induces apoptosis of pancreatic cancer cells. World J Gastroenterol 2008; 14:7192-8.
8. 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.
9. Rocha GZ, Dias MM, Ropelle ER, Osorio-Costa F, Rossato FA, Vercesi AE, et al. Metformin amplifies chemotherapyinduced AMPK activation and antitumoral growth. Clin Cancer Res 2011; 17:3993-4005.
10. Memmott RM, Mercado JR, Maier CR, Kawabata S, Fox SD, Dennis PA. Metformin prevents tobacco carcinogen-induced lung tumorigenesis. Cancer Prev Res (Phila) 2010;3:1066-76.
11. Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2001;108:1167-74. 14.
12. Dowling RJ, Zakikhani M, Fantus IG, Pollak M, Sonenberg N. Metformin inhibits mammalian target of rapamycindependent translation initiation in breast cancer cells. Cancer Res 2007;67:10804-12.
13. 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.
14. Morgillo F, Cascone T, D'Aiuto E, Martinelli E, Troiani T, Saintigny P, et al. Antitumour efficacy of MEK inhibitors in human lung cancer cells and their derivatives with acquired resistance to different tyrosine kinase inhibitors. Br J Cancer 2011;105:382-92.
15. Fremin C, Meloche S. From basic research to clinical development of MEK1/2 inhibitors for cancer therapy. J HematolOncol 2010;3:8-14.
16. Zhao Y, Adjei AA. The clinical development of MEK inhibitors. Nat Rev ClinOncol 2014;11:385-400.
17. Paolo M, Assunta S, Antonio R, Claudia SP, Anna BM, Clorinda S et al. Selumetinib in advanced non small cell lung cancer (NSCLC) harbouring KRAS mutation: endless clinical challenge to KRAS-mutant NSCLC. Rev Recent Clin Trials 2013;8:93-100.
18. Martinelli E, Troiani T, D'Aiuto E, Morgillo F, Vitagliano D, Capasso A, et al. Antitumor activity of pimasertib, a selective MEK 1/2 inhibitor, in combination with PI3K/mTOR inhibitors or with multi-targeted kinase inhibitors in pimasertib-resistant human lung and colorectal cancer cells. Int J Cancer 2013;133:2089-101.
19. Troiani T, Vecchione L, Martinelli E, Capasso A, Costantino S, Ciuffreda LP, et al. Intrinsic resistance to selumetinib, a selective inhibitor of MEK1/2, by cAMPdependent protein kinase A activation in human lung and colorectal cancer cells. Br J Cancer 2012;106:1648-59.
20. Jänne PA, Shaw AT, Pereira JR, Jeannin G, Vansteenkiste J, Barrios C et al. Selumetinib plus docetaxel for KRASmutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol 2013;14:38-47.
21. Jänne PA, Smith I, McWalter G, Mann H, Dougherty B, Walker J, et al. Impact of KRAS codon subtypes from a randomised phase II trial of selumetinib plus docetaxel in KRAS mutant advanced non-small-cell lung cancer.Br J Cancer. 2015 Jul 14;113:199-203.
22. Ohashi K, Sequist LV, Arcila ME, Lovly CM, Chen X, Rudin CM et al. Characteristics of lung cancers harboring NRAS mutations. Clin Cancer Res 2013;19:2584-91.
23. Chou TC, Talalay P. Quantitative analysis of dose effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 1984;22:27-55.
24. Yue D, Li H, Che J, Zhang Y, Tseng HH, Jin JQ, et al. Hedgehog/Gli promotes epithelial-mesenchymal transition in lung squamous cell carcinomas. J ExpClin Cancer Res 2014; 24:33-4.
25. Yoo YA, Kang MH, Lee HJ, Kim BH, Park JK, Kim HK, et al. Sonic hedgehog pathway promotes metastasis and lymphangiogenesis via activation of Akt, EMT, and MMP-9 pathway in gastric cancer. Cancer Res 2011;71:7061-70.
26. Maitah MY, Ali S, Ahmad A, Gadgeel S, Sarkar FH. Up-regulation of sonic hedgehog contributes to TGFβ1-induced epithelial to mesenchymal transition in NSCLC cells. PLoS One 2011;6:e16068.
27. D'Amato C, Rosa R, Marciano R, D'Amato V, Formisano L, Nappi L, et al. Inhibition of Hedgehog signalling by NVP-LDE225 (Erismodegib) interferes with growth and invasion of human renal cell carcinoma cells. Br J Cancer 2014;9;111:1168-79.
28. Della Corte CM, Bellevicine C, Vicidomini G, Vitagliano D, Malapelle U, Accardo M, et al. SMO gene amplification and activation of the hedgehog pathway as novel mechanisms of resistance to anti-epidermal growth factor receptor drugs in human lung cancer. Clin Cancer Res 2015; 21:4686-97.
29. Fan C, Wang Y, Liu Z, Sun Y, Wang X, Wei G, Wei J. Metformin exerts anticancer effects through the inhibition of the Sonic hedgehog signaling pathway in breast cancer. Int J Mol Med 2015;36:204-14.
30. Nakamura M, Ogo A, Yamura M, Yamaguchi Y, Nakashima H. Metformin suppresses sonic hedgehog expression in pancreatic cancer cells.Anticancer Res 2014;34:1765-9.
31. Hsieh SC, Tsai JP, Yang SF, Tang MJ, Hsieh YH. Metformin inhibits the invasion of human hepatocellular carcinoma cells and enhances the chemosensitivity to sorafenib through a downregulation of the ERK/JNKmediated NF-κB-dependent pathway that reduces uPA and MMP-9 expression. Amino Acids 2014;46:2809-22.
32. Schneider T, Osl F, Friess T, Stockinger H, Scheuer WV. Quantification of human Alu sequences by real-time PCR-an improved method to measure therapeutic efficacy of anti-metastatic drugs in human xenotransplants. ClinExp Metastasis 2002; 19: 571-82.
33. Fasano M, Della Corte CM, Capuano A, Sasso FC, Papaccio F, Berrino L, et al. A multicenter, open-label phase II study of metformin with erlotinib in second-line therapy of stage IV non-small-cell lung cancer patients: treatment rationale and protocol dynamics of the METAL trial. Clin Lung Cancer 2015;16:57-9.
34. Mimeault M, Batra SK. Frequent deregulations in the hedgehog signaling network and cross-talks with the epidermal growth factor receptor pathway involved in cancer progression and targeted therapies. Pharmacol Rev 2010;62:497-524.
35. Chen X, Lingala S, Khoobyari S, Nolta J, Zern MA, Wu J. Epithelial mesenchymal transition and hedgehog signaling activation are associated with chemoresistance and invasion of hepatoma subpopulations. J Hepatol 2011;55:838-45.
36. Mimeault M, Batra SK. Altered gene products involved in the malignant reprogramming of cancer stem/progenitor cells and multitargeted therapies. Mol Aspects Med 2014;39:3-32.
37. Tan BK, Adya R, Chen J, Lehnert H, Sant Cassia LJ, Randeva HS. Metformin treatment exerts antiinvasive and antimetastatic effects in human endometrial carcinoma cells. J Clin Endocrinol Metab 2011; 96:808-16.
38. Castellone MD, Laukkanen MO, Teramoto H, Bellelli R, Alì G, Fontanini G, et al. Cross talk between the bombesin neuropeptide receptor and Sonic hedgehog pathways in small cell lung carcinoma. Oncogene 2015;34:1679-87.
39. Tung MC, Hsieh SC, Yang SF, Cheng CW, Tsai RT, Wang SC, et al. Knockdown of lipocalin-2 suppresses the growth and invasion of prostate cancer cells. Prostate 2013;73:1281-90.
40. Tsai SJ, Hwang JM, Hsieh SC, Ying TH, Hsieh YH. Overexpression of myeloid zinc finger 1 suppresses matrix metalloproteinase-2 expression and reduces invasiveness of SiHa human cervical cancer cells. BiochemBiophys Res Commun 2012;425:462-7.
41. Tsai JP, Hsiao PC, Yang SF, Hsieh SC, Bau DT, Ling CL, et al.Licochalcone a suppresses migration and invasion of human hepatocellular carcinoma cells through downregulation of MKK4/JNK via NF-kappaB mediated urokinase plasminogen activator expression. PLoS One 2014:e86537.
42. Liu Z, Zhang B, Liu K, Ding Z, Hu X. Schisandrin B attenuates cancer invasion and metastasis via inhibiting epithelial-mesenchymal transition. PLoS One 2012;7: e40480.