Crosstalk Between Insulin/insulin-like Growth Factor-1 Receptors and G Protein-coupled Receptor Signaling Systems: a Novel Target for the Antidiabetic Drug Metformin in Pancreatic Cancer

Overview

Journal Clin Cancer Res

Specialty Oncology

Date 2010 Apr 15

PMID 20388847

Citations 123

Authors

Enrique Rozengurt

James Sinnett-Smith

Krisztina Kisfalvi

Affiliations

Soon will be listed here.

Abstract

Insulin/insulin-like growth factor 1(IGF-1) receptors and G protein-coupled receptors (GPCR) signaling systems are implicated in autocrine-paracrine stimulation of a variety of malignancies, including ductal adenocarcinoma of the pancreas, one of the most lethal human diseases. Novel targets for pancreatic cancer therapy are urgently needed. We identified a crosstalk between insulin/IGF-1 receptors and GPCR signaling systems in pancreatic cancer cells, leading to enhanced signaling, DNA synthesis, and proliferation. Crosstalk between these signaling systems depends on mammalian target of rapamycin (mTOR) complex 1 (mTORC1). Metformin, the most widely used drug in the treatment of type 2 diabetes, activates AMP kinase (AMPK), which negatively regulates mTORC1. Recent results show that metformin-induced activation of AMPK disrupts crosstalk between insulin/IGF-1 receptor and GPCR signaling in pancreatic cancer cells and inhibits the growth of these cells in xenograft models. Given that insulin/IGF-1 and GPCRs are implicated in other malignancies, a similar crosstalk mechanism may be operative in other cancer cell types. Recent epidemiological studies linked administration of metformin with a reduced risk of pancreatic, breast, and prostate cancer in diabetic patients. We posit that crosstalk between insulin/IGF-1 receptor and GPCR signaling is a mechanism for promoting the development of certain types of cancer and a target for the prevention and therapy of these diseases via metformin administration.

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References

Pawson T . Specificity in signal transduction: from phosphotyrosine-SH2 domain interactions to complex cellular systems. Cell. 2004; 116(2):191-203. DOI: 10.1016/s0092-8674(03)01077-8. View

Arafat H, Gong Q, Chipitsyna G, Rizvi A, Saa C, Yeo C . Antihypertensives as novel antineoplastics: angiotensin-I-converting enzyme inhibitors and angiotensin II type 1 receptor blockers in pancreatic ductal adenocarcinoma. J Am Coll Surg. 2007; 204(5):996-1005. DOI: 10.1016/j.jamcollsurg.2007.01.067. View

Grahame Hardie D . AMP-activated protein kinase as a drug target. Annu Rev Pharmacol Toxicol. 2006; 47:185-210. DOI: 10.1146/annurev.pharmtox.47.120505.105304. View

Dorsam R, Gutkind J . G-protein-coupled receptors and cancer. Nat Rev Cancer. 2007; 7(2):79-94. DOI: 10.1038/nrc2069. View

Sinnett-Smith J, Zhukova E, Hsieh N, Jiang X, Rozengurt E . Protein kinase D potentiates DNA synthesis induced by Gq-coupled receptors by increasing the duration of ERK signaling in swiss 3T3 cells. J Biol Chem. 2004; 279(16):16883-93. DOI: 10.1074/jbc.M313225200. View

Kisfalvi K, Eibl G, Sinnett-Smith J, Rozengurt E . Metformin disrupts crosstalk between G protein-coupled receptor and insulin receptor signaling systems and inhibits pancreatic cancer growth. Cancer Res. 2009; 69(16):6539-45. PMC: 2753241. DOI: 10.1158/0008-5472.CAN-09-0418. View

Kisfalvi K, Rey O, Young S, Sinnett-Smith J, Rozengurt E . Insulin potentiates Ca2+ signaling and phosphatidylinositol 4,5-bisphosphate hydrolysis induced by Gq protein-coupled receptor agonists through an mTOR-dependent pathway. Endocrinology. 2007; 148(7):3246-57. DOI: 10.1210/en.2006-1711. View

Kornmann M, Maruyama H, Bergmann U, Tangvoranuntakul P, Beger H, White M . Enhanced expression of the insulin receptor substrate-2 docking protein in human pancreatic cancer. Cancer Res. 1998; 58(19):4250-4. View

Inoki K, Guan K . Complexity of the TOR signaling network. Trends Cell Biol. 2006; 16(4):206-12. DOI: 10.1016/j.tcb.2006.02.002. View

10.

Giovannucci E, Michaud D . The role of obesity and related metabolic disturbances in cancers of the colon, prostate, and pancreas. Gastroenterology. 2007; 132(6):2208-25. DOI: 10.1053/j.gastro.2007.03.050. View

11.

Bierkamp C, Bonhoure S, Mathieu A, Clerc P, Fourmy D, Pradayrol L . Expression of cholecystokinin-2/gastrin receptor in the murine pancreas modulates cell adhesion and cell differentiation in vivo. Am J Pathol. 2004; 165(6):2135-45. PMC: 1618719. DOI: 10.1016/S0002-9440(10)63263-4. View

12.

Inoki K, Ouyang H, Zhu T, Lindvall C, Wang Y, Zhang X . TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell. 2006; 126(5):955-68. DOI: 10.1016/j.cell.2006.06.055. View

13.

Chong C, Chabner B . Mysterious metformin. Oncologist. 2009; 14(12):1178-81. DOI: 10.1634/theoncologist.2009-0286. View

14.

Jia S, Roberts T, Zhao J . Should individual PI3 kinase isoforms be targeted in cancer?. Curr Opin Cell Biol. 2009; 21(2):199-208. PMC: 3142565. DOI: 10.1016/j.ceb.2008.12.007. View

15.

Gwinn D, Shackelford D, Egan D, Mihaylova M, Mery A, Vasquez D . AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell. 2008; 30(2):214-26. PMC: 2674027. DOI: 10.1016/j.molcel.2008.03.003. View

16.

Kisfalvi K, Hurd C, Guha S, Rozengurt E . Induced overexpression of protein kinase D1 stimulates mitogenic signaling in human pancreatic carcinoma PANC-1 cells. J Cell Physiol. 2010; 223(2):309-16. PMC: 2888293. DOI: 10.1002/jcp.22036. View

17.

Reubi J, Waser B, Friess H, Buchler M, Laissue J . Neurotensin receptors: a new marker for human ductal pancreatic adenocarcinoma. Gut. 1998; 42(4):546-50. PMC: 1727058. DOI: 10.1136/gut.42.4.546. View

18.

Sun Y, Fang Y, Yoon M, Zhang C, Roccio M, Zwartkruis F . Phospholipase D1 is an effector of Rheb in the mTOR pathway. Proc Natl Acad Sci U S A. 2008; 105(24):8286-91. PMC: 2448829. DOI: 10.1073/pnas.0712268105. View

19.

Yuan T, Cantley L . PI3K pathway alterations in cancer: variations on a theme. Oncogene. 2008; 27(41):5497-510. PMC: 3398461. DOI: 10.1038/onc.2008.245. View

20.

Schneider M, Matsuzaki H, Haorah J, Ulrich A, Standop J, Ding X . Prevention of pancreatic cancer induction in hamsters by metformin. Gastroenterology. 2001; 120(5):1263-70. DOI: 10.1053/gast.2001.23258. View