K‑ras gene mutation as a predictor of cancer cell responsiveness to metformin

Ma,Yu; Guo,Fu‑Chun; Wang,Wei; Shi,Hua‑Shan; Li,Dan; Wang,Yong‑Sheng

doi:10.3892/mmr.2013.1596

K‑ras gene mutation as a predictor of cancer cell responsiveness to metformin

Authors:
- Yu Ma
- Fu‑Chun Guo
- Wei Wang
- Hua‑Shan Shi
- Dan Li
- Yong‑Sheng Wang
View Affiliations

Affiliations: Department of Thoracic Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
Published online on: July 22, 2013 https://doi.org/10.3892/mmr.2013.1596
Pages: 763-768

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

An increasing number of studies support the use of metformin, a common antidiabetic drug, as a novel anticancer therapeutic. However, its mechanism of action has yet to be identified. In the current study, metformin was observed to effectively inhibit the growth of the K‑ras mutant but not wild‑type tumors in vivo. The antitumor effects of metformin were mediated by the induction of apoptosis and inhibition of proliferation in vivo. In addition, metformin induced apoptosis in the K‑ras mutant tumors, A549 and PANC‑1, but not in the K‑ras wild‑type tumor, A431, in vitro. Similarly, at lower concentrations, metformin inhibited cell proliferation in the K‑ras mutant, but not in the K‑ras wild‑type tumor cells in vitro. These observations indicate that tumors with K‑ras mutations are sensitive to metformin therapy. In addition, metformin significantly arrested K‑ras mutant and wild‑type tumor cells in G1 phase in vitro and metformin downregulated two important downstream effectors of the Ras signaling pathway in K‑ras mutant tumors. Metformin was concluded to function as a potential K‑ras‑targeting agent that has potential for cancer therapy.

View Figures

View References

1	Vigneri P, Frasca F, Sciacca L, Pandini G and Vigneri R: Diabetes and cancer. Endocr Relat Cancer. 16:1103–1123. 2009. View Article : Google Scholar
2	Gallagher EJ and LeRoith D: Insulin, insulin resistance, obesity, and cancer. Curr Diab Rep. 10:93–100. 2010. View Article : Google Scholar
3	Martin-Castillo B, Vazquez-Martin A, Oliveras-Ferraros C and Menendez JA: Metformin and cancer: doses, mechanisms and the dandelion and hormetic phenomena. Cell Cycle. 9:1057–1064. 2010. View Article : Google Scholar : PubMed/NCBI
4	Gonzalez-Angulo AM and Meric-Bernstam F: Metformin: a therapeutic opportunity in breast cancer. Clin Cancer Res. 16:1695–1700. 2010. View Article : Google Scholar : PubMed/NCBI
5	Zakikhani M, Dowling R, Fantus IG, Sonenberg N and Pollak M: Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res. 66:10269–10273. 2006. View Article : Google Scholar : PubMed/NCBI
6	Jones RG, Plas DR, Kubek S, et al: AMP-Activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell. 18:283–293. 2005. View Article : Google Scholar : PubMed/NCBI
7	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 : PubMed/NCBI
8	Kisfalvi K, Sinnett-Smith J, Eibl G and Rozengurt E: Metformin inhibits growth of human pancreatic cancer cells in vitro and in vivo. Pancreas. 38:1016–1017. 2009.
9	Bodmer M, Becker C, Jick SS and Meier CR: Metformin does not alter the risk of lung cancer: a case-control analysis. Lung Cancer. 78:133–137. 2012. View Article : Google Scholar : PubMed/NCBI
10	Bodmer M, Becker C, Meier C, Jick SS and Meier CR: Use of metformin is not associated with a decreased risk of colorectal cancer: a case-control analysis. Cancer Epidemiol Biomarkers Prev. 21:280–286. 2012. View Article : Google Scholar : PubMed/NCBI
11	Buzzai M, Jones RG, Amaravadi RK, et al: Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res. 67:6745–6752. 2007. View Article : Google Scholar : PubMed/NCBI
12	Reuter CW, Morgan MA and Bergmann L: Targeting the Ras signaling pathway: a rational, mechanism-based treatment for hematologic malignancies? Blood. 96:1655–1669. 2000.PubMed/NCBI
13	Cox AD and Der CJ: Ras family signaling: therapeutic targeting. Cancer Biol Ther. 1:599–606. 2002. View Article : Google Scholar : PubMed/NCBI
14	Friday BB and Adjei AA: K-ras as a target for cancer therapy. Biochim Biophys Acta. 1756:127–144. 2005.PubMed/NCBI
15	Legaspi A, Jeevanandam M, Starnes HF Jr and Brennan MF: Whole body lipid and energy metabolism in the cancer patient. Metabolism. 36:958–963. 1987. View Article : Google Scholar : PubMed/NCBI
16	Blum R and Kloog Y: Tailoring Ras-pathway - inhibitor combinations for cancer therapy. Drug Resist Updat. 8:369–380. 2005. View Article : Google Scholar : PubMed/NCBI
17	Skolnik EY, Batzer A, Li N, et al: The function of GRB2 in linking the insulin receptor to Ras signaling pathways. Science. 260:1953–1955. 1993. View Article : Google Scholar : PubMed/NCBI
18	Noguchi T, Matozaki T, Horita K, Fujioka Y and Kasuga M: Role of SH-PTP2, a protein-tyrosine phosphatase with Src homology 2 domains, in insulin-stimulated Ras activation. Mol Cell Biol. 14:6674–6682. 1994.PubMed/NCBI
19	Desbois-Mouthon C, Cadoret A, Blivet-Van Eggelpoël MJ, et al: Insulin and IGF-1 stimulate the beta-catenin pathway through two signalling cascades involving GSK-3beta inhibition and Ras activation. Oncogene. 20:252–259. 2001. View Article : Google Scholar : PubMed/NCBI
20	Medema RH, de Vries-Smits AM, van der Zon GC, Maassen JA and Bos JL: Ras activation by insulin and epidermal growth factor through enhanced exchange of guanine nucleotides on p21ras. Mol Cell Biol. 13:155–162. 1993.PubMed/NCBI
21	Lehman TA, Bennett WP, Metcalf RA, et al: p53 mutations, ras mutations and p53-heat shock 70 protein complexes in human lung carcinoma cell lines. Cancer Res. 51:4090–4096. 1991.PubMed/NCBI
22	Watanabe M, Nobuta A, Tanaka J and Asaka M: An effect of K-ras gene mutation on epidermal growth factor receptor signal transduction in PANC-1 pancreatic carcinoma cells. Int J Cancer. 67:264–268. 1996. View Article : Google Scholar : PubMed/NCBI
23	Oliveras-Ferraros C, Cufi S, Queralt B, et al: Cross-suppression of EGFR ligands amphiregulin and epiregulin and de-repression of FGFR3 signalling contribute to cetuximab resistance in wild-type KRAS tumour cells. Br J Cancer. 106:1406–1414. 2012. View Article : Google Scholar : PubMed/NCBI
24	Iivanainen E, Lauttia S, Zhang N, et al: The EGFR inhibitor gefitinib suppresses recruitment of pericytes and bone marrow-derived perivascular cells into tumor vessels. Microvasc Res. 78:278–285. 2009. View Article : Google Scholar : PubMed/NCBI
25	Bartrons R and Caro J: Hypoxia, glucose metabolism and the Warburg’s effect. J Bioenerg Biomembr. 39:223–229. 2007.
26	Feig LA and Buchsbaum RJ: Cell signaling: life or death decisions of ras proteins. Curr Biol. 12:R259–R261. 2002. View Article : Google Scholar : PubMed/NCBI
27	Ferla R, Haspinger E and Surmacz E: Metformin inhibits leptin-induced growth and migration of glioblastoma cells. Oncol Lett. 4:1077–1081. 2012.PubMed/NCBI
28	Adjei AA: Blocking oncogenic Ras signaling for cancer therapy. J Natl Cancer Inst. 93:1062–1074. 2001. View Article : Google Scholar : PubMed/NCBI
29	Wang W and Guan KL: AMP-activated protein kinase and cancer. Acta Physiol (Oxf). 196:55–63. 2009. View Article : Google Scholar
30	Carling D: AMP-activated protein kinase: balancing the scales. Biochimie. 87:87–91. 2005. View Article : Google Scholar : PubMed/NCBI
31	Mahoney CL, Choudhury B, Davies H, et al: LKB1/KRAS mutant lung cancers constitute a genetic subset of NSCLC with increased sensitivity to MAPK and mTOR signalling inhibition. Br J Cancer. 100:370–375. 2009. View Article : Google Scholar : PubMed/NCBI
32	Ben Sahra I, Regazzetti C, Robert G, et al: Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1. Cancer Res. 71:4366–4372. 2011.PubMed/NCBI
33	Kalender A, Selvaraj A, Kim SY, et al: Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab. 11:390–401. 2010. View Article : Google Scholar : PubMed/NCBI
34	Cox AD and Der CJ: Farnesyltransferase inhibitors: promises and realities. Curr Opin Pharmacol. 2:388–393. 2002. View Article : Google Scholar : PubMed/NCBI
35	Li D: Metformin as an antitumor agent in cancer prevention and treatment. J Diabetes. 3:320–327. 2011. View Article : Google Scholar : PubMed/NCBI