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.
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.
Rozengurt
Enrique
E
Department of Medicine, CURE: Digestive Diseases Research Center, David Geffen School of Medicine and Molecular Biology Institute, University of California at Los Angeles, Los Angeles, California 90095-1786, USA. erozengurt@mednet.ucla.edu
Sinnett-Smith
James
J
Kisfalvi
Krisztina
K
D000818:Animals; D002986:Clinical Trials as Topic; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000076222:Mechanistic Target of Rapamycin Complex 1; D008687:Metformin / Q000494:pharmacology* / Q000627:therapeutic use; D008954:Models, Biological; D046912:Multiprotein Complexes; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D011506:Proteins; D020239:Receptor Cross-Talk / Q000187:drug effects*; D017526:Receptor, IGF Type 1 / Q000502:physiology*; D011972:Receptor, Insulin / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000502:physiology
D007004:Hypoglycemic Agents; D046912:Multiprotein Complexes; D011506:Proteins; D043562:Receptors, G-Protein-Coupled; D014157:Transcription Factors; D008687:Metformin; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
Cell. 2004 Jan 23;116(2):191-203
14744431
J Am Coll Surg. 2007 May;204(5):996-1005; discussion 1005-6
17481528
Annu Rev Pharmacol Toxicol. 2007;47:185-210
16879084
Nat Rev Cancer. 2007 Feb;7(2):79-94
17251915
J Biol Chem. 2004 Apr 16;279(16):16883-93
14963034
Cancer Res. 2009 Aug 15;69(16):6539-45
19679549
Endocrinology. 2007 Jul;148(7):3246-57
17379645
Cancer Res. 1998 Oct 1;58(19):4250-4
9766646
Trends Cell Biol. 2006 Apr;16(4):206-12
16516475
Gastroenterology. 2007 May;132(6):2208-25
17498513
Am J Pathol. 2004 Dec;165(6):2135-45
15579455
Cell. 2006 Sep 8;126(5):955-68
16959574
Oncologist. 2009 Dec;14(12):1178-81
20007645
Curr Opin Cell Biol. 2009 Apr;21(2):199-208
19200708
Mol Cell. 2008 Apr 25;30(2):214-26
18439900
J Cell Physiol. 2010 May;223(2):309-16
20082306
Gut. 1998 Apr;42(4):546-50
9616318
Proc Natl Acad Sci U S A. 2008 Jun 17;105(24):8286-91
18550814
Oncogene. 2008 Sep 18;27(41):5497-510
18794884
Gastroenterology. 2001 Apr;120(5):1263-70
11266389
J Clin Invest. 2008 Nov;118(11):3790-7
18846254
Cell. 2007 Jun 1;129(5):957-68
17540175
Cancer Cell. 2004 Jul;6(1):91-9
15261145
Curr Opin Cell Biol. 2005 Dec;17(6):596-603
16226444
Cancer Res. 2005 Apr 1;65(7):2738-45
15805273
Gastroenterology. 2009 Aug;137(2):482-8
19375425
Biochem Biophys Res Commun. 2005 May 27;331(1):295-302
15845392
Science. 1986 Oct 10;234(4773):161-6
3018928
Mol Endocrinol. 2006 May;20(5):953-70
16141358
J Cell Physiol. 2007 Dec;213(3):589-602
17786953
J Biol Chem. 2005 Apr 8;280(14):13205-8
15701647
Trends Cell Biol. 2002 Feb;12(2):65-71
11849969
Nat Rev Mol Cell Biol. 2006 Feb;7(2):85-96
16493415
J Cell Biochem. 2008 Feb 1;103(2):648-62
17570131
Diabetes Care. 2009 Sep;32(9):1620-5
19564453
Cancer Res. 2006 Nov 1;66(21):10269-73
17062558
Oncogene. 2008 Nov 24;27(55):6908-19
19029933
Cancer Res. 2003 May 15;63(10):2379-87
12750255
J Biol Chem. 2009 May 15;284(20):13434-13445
19289471
Mol Cell. 2003 Jun;11(6):1457-66
12820960
Clin Cancer Res. 2000 Feb;6(2):566-71
10690540
Cancer Res. 2007 Nov 15;67(22):10804-12
18006825
Cancer Res. 2007 Jul 15;67(14):6745-52
17638885
Cell. 2003 Nov 26;115(5):577-90
14651849
Cancer Res. 2007 May 15;67(10):4679-86
17510394
J Cell Physiol. 2005 Mar;202(3):880-90
15389644
Cell Signal. 2007 Jun;19(6):1348-57
17307332
Cell Metab. 2006 Jun;3(6):393-402
16753575
Oncogene. 2003 Dec 4;22(55):8939-47
14654790
PLoS One. 2010 Jan 21;5(1):e8824
20098680
Cancer Res. 2009 Oct 1;69(19):7507-11
19752085
Cancer Res. 2007 Aug 15;67(16):7551-5
17699757
Cancer Res. 2002 Mar 15;62(6):1632-40
11912133
Cell Metab. 2005 Jan;1(1):15-25
16054041
Cancer Res. 2005 Oct 15;65(20):9164-8
16230374
Nat Cell Biol. 2003 Jun;5(6):578-81
12771962
J Cell Physiol. 2001 Jan;186(1):53-64
11147814
Anticancer Res. 2000 Jan-Feb;20(1A):53-8
10769634
Science. 2005 Dec 9;310(5754):1642-6
16308421
Cell. 2006 Feb 10;124(3):471-84
16469695