Mechanism of metformin-dependent inhibition of mammalian target of rapamycin (mTOR) and Ras activity in pancreatic cancer

Journal of Biological Chemistry

Volumn 289, Issue 40, 2014, Pages 27692-27701

  Nair, Vijayalekshmi ^a   Sreevalsan, Sandeep ^a   Basha, Riyaz ^b,c   Abdelrahlm, Maen ^b,c   Abudayyeh, Ala ^d   Hoffman, Aline Rodrigues ^a   Safe, Stephen ^a,e  

^a TEXAS A AND M UNIVERSITY   (United States)

^b M D ANDERSON CANCER CENTER ORLANDO   (United States)

^c BAYLOR COLLEGE OF MEDICINE   (United States)

^d UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER   (United States)

^e TEXAS A AND M HEALTH SCIENCE CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CELL SIGNALING; CELLS; DISEASES; GENES; MAMMALS; TRANSCRIPTION;

ANTI-DIABETIC DRUGS; ANTINEOPLASTIC ACTIVITY; CHEMOTHERAPEUTIC ACTIVITY; EPIDERMAL GROWTH FACTORS; INSULIN-LIKE GROWTH FACTOR-1 RECEPTORS; MAMMALIAN TARGET OF RAPAMYCIN (MTOR); MECHANISM OF ACTION; ONCOGENIC PATHWAYS;

ANTIBIOTICS;

EPIDERMAL GROWTH FACTOR RECEPTOR; MAMMALIAN TARGET OF RAPAMYCIN; METFORMIN; PLACEBO; RAS PROTEIN; SOMATOMEDIN C RECEPTOR; TRANSCRIPTION FACTOR SP1; TRANSCRIPTION FACTOR SP3; TRANSCRIPTION FACTOR SP4; ANTINEOPLASTIC AGENT; MTOR PROTEIN, HUMAN; TARGET OF RAPAMYCIN KINASE; TRANSCRIPTION FACTOR SP;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTINEOPLASTIC ACTIVITY; ARTICLE; CELLULAR DISTRIBUTION; CONCENTRATION RESPONSE; CONTROLLED STUDY; DOWN REGULATION; DRUG MECHANISM; DRUG PROTEIN BINDING; DRUG TARGETING; GENE SILENCING; HUMAN; HUMAN CELL; MALE; MOUSE; MOUSE MODEL; NONHUMAN; ORTHOTOPIC TRANSPLANTATION; PANCREAS CANCER; PANCREATIC CANCER CELL LINE; PROTEIN DETERMINATION; PROTEIN EXPRESSION; PROTEIN LOCALIZATION; RNA INTERFERENCE; SIGNAL TRANSDUCTION; TRANSCRIPTION REGULATION; ANIMAL; ANTAGONISTS AND INHIBITORS; DRUG EFFECTS; GENE EXPRESSION REGULATION; GENETICS; METABOLISM; NUDE MOUSE; PANCREATIC NEOPLASMS; TUMOR CELL LINE;

ANIMALS; ANTINEOPLASTIC AGENTS; CELL LINE, TUMOR; DOWN-REGULATION; GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS; MALE; METFORMIN; MICE; MICE, NUDE; PANCREATIC NEOPLASMS; RAS PROTEINS; SIGNAL TRANSDUCTION; SP TRANSCRIPTION FACTORS; TOR SERINE-THREONINE KINASES;

EID: 84907495391     PISSN: 00219258     EISSN: 1083351X     Source Type: Journal    
DOI: 10.1074/jbc.M114.592576     Document Type: Article

References (51)

1. Pollak, M. (2010) Metformin and other biguanides in oncology: Advancing the research agenda. Cancer Prev. Res. (Phila.) 3,1060 -1065
2. Ben Sahra, I, Le Marchand-Brustel, Y., Tanti, J. F., and Bost, F. (2010) Metformin in cancer therapy: A new perspective for an old antidiabetic drug? Mol. Cancer Ther. 9,1092-1099
3. Engelman, J. A., and Cantley, L. C. (2010) Chemoprevention meets glucose control. Cancer Prev. Res. (Phila.) 3,1049 -1052
4. Dowling, R. J., Niraula, S., Stambolic, V., and Goodwin, P. J. (2012) Metformin in cancer: Translational challenges.J. Mol. Endocrinol. 48, R31-R43
5. Evans,J. M., Donnelly, L. A., Emslie-Smith, A. M., Alessi, D. R., and Morris, A. D. (2005) Metformin and reduced risk of cancer in diabetic patients. BMJ 330,1304-1305
6. Garrett, C. R., Hassabo, H. M., Bhadkamkar, N. A., Wen, S., Baladandayuthapani, V., Kee, B. K., Eng, C., and Hassan, M. M. (2012) Survival advantage observed with the use of metformin in patients with type II diabetes and colorectal cancer. Br. J. Cancer 106,1374-1378
7. Jiralerspong, S., Palla, S. L., Giordano, S. H., Meric-Bernstam, F., Liedtke, C., Barnett, C. M., Hsu, L., Hung, M. C., Hortobagyi, G. N., and Gonzalez-Anguio, A. M. (2009) Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer.J. Clin. Oncol. 27, 3297-3302
8. Libby, G., Donnelly, L. A., Donnan, P. T., Alessi, D. R., Morris, A. D., and Evans, J. M. (2009) New users of metformin are at low risk of incident cancer: A cohort study among people with type 2 diabetes. Diabetes Care 32,1620-1625
9. Murtola, T. J., Tammela, T. L., Lahtela, J., and Auvinen, A. (2008) Antidiabetic medication and prostate cancer risk: a population-based case-control study. Am. J. Epidemiol. 168, 925-931
10. Sadeghi, N., Abbruzzese, J. L., Yeung, S. C., Hassan, M., and Li, D. (2012) Metformin use is associated with better survival of diabetic patients with pancreatic cancer. Clin. Cancer Res. 18, 2905-2912
11. Spillane, S., Bennett, K., Sharp, L., and Barron, T. I. (2013) A cohort study of metformin exposure and survival in patients with stage I-III colorectal cancer. Cancer Epidemiol. Biomarkers Prev. 22,1364-1373
12. Wright, J. L., and Stanford, J. L. (2009) Metformin use and prostate cancer in Caucasian men: results from a population-based case-control study. Cancer Causes Control 20,1617-1622
13. Ben Sahra, L, Laurent, K., Loubat, A., Giorgetti-Peraldi, S., Colosetti, P., Auberger, P., Tanti, J. F., Le Marchand-Brustel, Y., and Bost, F. (2008) The anti diabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level. Oncogene 27, 3576-3586
14. Ben Sahra, L, Regazzetti, C., Robert, G., Laurent, K., Le Marchand-Brustel, Y., Auberger, P., Tanti, J. F., Giorgetti-Peraldi, S., and Bost, F. (2011) Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1. Cancer Res. 71, 4366-4372
15. Buzzai, M., Jones, R. G., Amaravadi, R. K., Lum, J. J., DeBerardinis, R. J., Zhao, F., Viollet, B., and Thompson, C. B. (2007) Systemic treatment with the anti diabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res. 67, 6745-6752
16. Cerezo, M., Tichet, M., Abbe, P., Ohanna, M., Lehraiki;, A., Rouaud, F., Allegra, M., Giacchero, D., Bahadoran, P., Bertolotto, C., Tartare-Deckert, S., Ballotti, R., and Rocchi, S. (2013) Metformin blocks melanoma invasion and metastasis development in AMPK/p53-dependent manner. Mol. Cancer Ther. 12,1605-1615
17. Gotlieb, W. H., Saumet, J., Beauchamp, M. C., Gu, J., Lau, S., Pollak, M. N., and Bruchim, I. (2008) In vitro metformin anti-neoplastic activity in epithelial ovarian cancer. Gynecol. Oncol. 110, 246-250
18. Gou, S., Cui, P., Li, X., Shi, P., Liu, T., and Wang, C. (2013) Low concentrations of metformin selectively inhibit CD133+ cell proliferation in pancreatic cancer and have anticancer action. PLoS One 8, e63969
19. Karnevi, E., Said, K., Andersson, R., and Rosendahl, A. H. (2013) Metformin-mediated growth inhibition involves suppression of the IGF-I receptor signalling pathway in human pancreatic cancer cells. BMC Cancer 13, 235
20. Kim, H. G., Hien, T. T., Han, E. H., Hwang, Y. P., Choi, J. H., Kang, K. W., Kwon, K. I, Kim, B. H., Kim, S. K., Song, G. Y., Jeong, T. C., and Jeong, H. G. (2011) Metformin inhibits P-glycoprotein expression via the NF-kB pathway and CRE transcriptional activity through AMPK activation. Br. J. Pharmacol. 162, 1096-1108
21. Kisfalvi, K., Eibl, G., Sinnett-Smith, J., and Rozengurt, E. (2009) Metformin disrupts crosstalk between G protein-coupled receptor and insulin receptor signaling systems and inhibits pancreatic cancer growth. Cancer Res. 69,6539-6545
22. Rozengurt, E., Sinnett-Smith, J., and Kisfalvi, K. (2010) Crosstalk between insulin/insulin-like growth factor-1 receptors and G protein-coupled re-ceptor signaling systems: A novel target for the anti diabetic drug metformin in pancreatic cancer. Clin. Cancer Res. 16, 2505-2511
23. Sinnett-Smith, J., Kisfalvi, K., Kui, R., and Rozengurt, E. (2013) Metformin inhibition of mTORC1 activation, DNA synthesis and proliferation in pancreatic cancer cells: Dependence on glucose concentration and role of AMPK. Biochem. Biophys. Res. Commun. 430, 352-357
24. Soares, H. P., Ni, Y., Kisfalvi, K., Sinnett-Smith, J., and Rozengurt, E. (2013) Different patterns of Akt and ERIC feedback activation in response to rapamycin, active-site mTOR inhibitors and metformin in pancreatic cancer cells. PLoS One 8, e57289
25. Storozhuk, Y., Hopmans, S. N., Sank, T., Barron, C., Tsiani, E., Cutz, J. C., Pond, G., Wright, J., Singh, G., and Tsakiridis, T. (2013) Metformin inhibits growth and enhances radiation response of non-small cell lung cancer (NSCLC) through ATM and AMPK. Br. J. Cancer 108, 2021-2032
26. Tan, B. K., Adya, R., Chen, J., Lehnert, H., Sant Cassia, L. J., and Ran deva, H. S. (2011) Metformin treatment exerts antiinvasive and antimetastatic effects in human endometrial carcinoma cells.J. Clin. Endocrinol. Metab. 96, 808-816
27. Yasmeen, A., Beauchamp, M. C., Piura, E., Segal, E., Pollak, M., and Gotlieb, W. H. (2011) Induction of apoptosis by metformin in epithelial ovarian cancer: involvement of the Bcl-2 family proteins. Gynecol. Oncol. 121, 492-498
28. Zhuang, Y., and Miskimins, W. K. (2011) Metformin induces both caspase-dependent and poly(ADP-ribose) polymerase-dependent cell death in breast cancer cells. Mol. Cancer Res. 9, 603-615
29. Shaw, R. J., Lamia, K. A., Vasquez, D., Koo, S. H., Bardeesy, N., Depinho, R. A., Montminy, M., and Cantley, L. C. (2005) The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310,1642-1646
30. Zou, M. H., Kirkpatrick, S. S., Davis, B. J., Nelson, J. S., Wiles, W. G., 4th, Schlattner, U., Neumann, D., Brownlee, M., Freeman, M. B., and Goldman, M. H. (2004) Activation of the AMP-activated protein kinase by the anti-diabetic drug metformin in vivo: role of mitochondrial reactive nitrogen species.J Biol. Chem. 279, 43940-43951
31. Nair, V., Pathi, S., Jutooru, I, Sreevalsan, S., Basha, R., Abdelrahim, M., Samudio, I, and Safe, S. (2013) Metformin inhibits pancreatic cancer cell and tumor growth and downregulates Sp transcription factors. Carcinogenesis 34, 2870-2879
32. Abdelrahim, M., Baker, C. H., Abbruzzese, J. L., Sheikh-Hamad, D., Liu, S., Cho, S. D., Yoon, K., and Safe, S. (2007) Regulation of vascular endothelial growth factor receptor-1 expression by specificity proteins 1, 3, and 4 in pancreatic cancer cells. Cancer Res. 67, 3286-3294
33. Abdelrahim, M., Smith, R., 3rd, Burghardt, R., and Safe, S. (2004) Role of Sp proteins in regulation of vascular endothelial growth factor expression and proliferation of pancreatic cancer cells. Cancer Res. 64, 6740-6749
34. Jutooru, I, Chadalapaka, G., Abdelrahim, M., Basha, M. R., Samudio, L, Konopleva, M., Andreeff, M., and Safe, S. (2010) Methyl 2-cyano-3,12-dioxooleana-l,9-dien-28-oate decreases specificity protein transcription factors and inhibits pancreatic tumor growth: role of microRNA-27a. Mol. Pharmacol. 78, 226-236
35. kB and pancreatic cancer cell and tumor growth by cur cumin is dependent on specificity protein down-regulation. J. Biol. Chem. 285, 25332-25344
36. Sreevalsan, S., and Safe, S. (2013) The cannabinoid WIN 55,212-2 decreases specificity protein transcription factors and the oncogenic cap protein eIF4E in colon cancer cells. Mol. Cancer Ther. 12, 2483-2493
37. Ardito, C. M., Grüner, B. M., Takeuchi, K. K., Lubeseder-Martellato, C.,Teichmann, N., Mazur, P. K., Delgiorno, K. E., Carpenter, E. S., Halbrook, C. J., Hall, J. C., Pal, D., Briel, T., Herner, A., Trajkovic-Arsic, M., Sipos, B., Liou, G. Y., Storz, P., Murray, N. R., Threadgill, D. W., Sibilia, M., Washington, M. K., Wilson, C. L., Schmid, R. M., Raines, E. W., Crawford, H. C., and Siveke, J. T. (2012) EGF receptor is required for KRAS-induced pancreatic tumorigenesis. Cancer Cell 22, 304-317
38. Navas, C., Hernández-Porras, I, Schuhmacher, A. J., Sibilia, M., Guerra, C., and Barbacid, M. (2012) EGF receptor signaling is essential for K -RAS oncogene-driven pancreatic ductal adenocarcinoma. Cancer Cell 22, 318-330
39. Chadalapaka, G., Jutooru, I, Burghardt, R., and Safe, S. (2010) Drugs that target specificity proteins downregulate epidermal growth factor receptor in bladder cancer cells. Mol. Cancer Res. 8, 739 -750
40. Furuta, E., Pai, S. K., Zhan, R., Bandyopadhyay, S., Watabe, M., Mo, Y. Y., Hirota, S., Hosobe, S., Tsukada, T., Miura, K., Kamada, S., Salto, K., Iiizumi, M., Liu, W., Ericsson, J., and Watabe, K. (2008) Fatty acid synthase gene is up-regulated by hypoxia via activation of Akt and sterol regulatory element binding protein-1. Cancer Res. 68,1003-1011
41. Owen, J. L., Zhang, Y., Bae, S. H., Farooqi, M. S., Liang, G., Hammer, R. E., Goldstein, J. L., and Brown, M. S. (2012) Insulin stimulation of SREBP-1c processing in transgenic rat hepatocytes requires p70 S6-kinase. Proc. Natl. Acad. Sci. U.S.A. 109,16184-16189
42. Porstmann, T., Santos, C. R., Griffiths, B., Cully, M., Wu, M., Leevers, S., Griffiths, J. R., Chung, Y. L., and Schulze, A. (2008) SREBP activity is regulated by mTORCl and contributes to Akt-dependent cell growth. Cell Metab. 8, 224-236
43. Lu, S., and Archer, M. C. (2010) Spl coordinately regulates de novo lipogenesis and proliferation in cancer cells. Int. J. Cancer 126, 416-425
44. Bergmann, U., Funatomi, H., Yokoyama, M., Beger, H. G., and Kore, M. (1995) Insulin-like growth factor I overexpression in human pancreatic cancer: Evidence for autocrine and paracrine roles. Cancer Res. 55, 2007-2011
45. Beitner-Johnson, D., Werner, H., Roberts, C. T., Jr., and LeRoith, D. (1995) Regulation of insulin-like growth factor I receptor gene expression by Spl: Physical and functional interactions of Spl at GC boxes and at a CT element. Mol. Endocrinol. 9,1147-1156
46. Wang, L. W., Li, Z. S., Zou, D. W., Jin, Z. D., Gao, J., and Xu, G. M. (2008) Metformin induces apoptosis of pancreatic cancer cells. World J. Gastroenterol. 14,7192-7198
47. Johnson, A. C., Ishii, S., Jinno, Y., Pastan, I, and Merlino, G. T. (1988) Epidermal growth factor receptor gene promoter: Deletion analysis and identification of nuclear protein binding sites. J. Biol. Chem. 263, 5693-5699
48. American Cancer Society (2011) Cancer Facts & Figures 2011, American Cancer Society, Atlanta, GA
49. Jutooru, I, Guthrie, A. S., Chadalapaka, G., Pathi, S., Kim, K., Burghardt, R., Jin, U. H., and Safe, S. (2014) Mechanism of action of phenethylisothiocyanate and other reactive oxygen species-inducing anti cancer agents. Mol. Cell. Biol. 34, 2382-2395
50. Jiang, N. Y., Woda, B. A., Banner, B. F., Whalen, G. F., Dresser, K. A., and Lu, D. (2008) Spl, a new biomarker that identifies a subset of aggressive pancreatic ductal adenocarcinoma. Cancer Epidemiol. Biomarkers Prev. 17,1648-1652
51. Deniaud, E., Baguet, J., Mathieu, A.L., Pagès, G., Marvel, J., and Leverrier, Y. (2006) Overexpression of Spl transcription factor induces apoptosis.Oncogene25, 7096-7105