PMID- 20388847 OWN - NLM STAT- MEDLINE DCOM- 20100820 LR - 20220330 IS - 1557-3265 (Electronic) IS - 1078-0432 (Print) IS - 1078-0432 (Linking) VI - 16 IP - 9 DP - 2010 May 1 TI - 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. PG - 2505-11 LID - 10.1158/1078-0432.CCR-09-2229 [doi] AB - 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. CI - Copyright 2010 AACR. FAU - Rozengurt, Enrique AU - Rozengurt E AD - 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 FAU - Sinnett-Smith, James AU - Sinnett-Smith J FAU - Kisfalvi, Krisztina AU - Kisfalvi K LA - eng GR - R01 DK55003/DK/NIDDK NIH HHS/United States GR - R01 DK055003/DK/NIDDK NIH HHS/United States GR - P30 DK41301/DK/NIDDK NIH HHS/United States GR - R21CA137292/CA/NCI NIH HHS/United States GR - R01 DK056930/DK/NIDDK NIH HHS/United States GR - P30 DK041301/DK/NIDDK NIH HHS/United States GR - R21 CA137292-01A1/CA/NCI NIH HHS/United States GR - R01 DK055003-11/DK/NIDDK NIH HHS/United States GR - R01 DK056930-09/DK/NIDDK NIH HHS/United States GR - P30 DK041301-21/DK/NIDDK NIH HHS/United States GR - R21 CA137292/CA/NCI NIH HHS/United States GR - R01 DK56930/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20100413 PL - United States TA - Clin Cancer Res JT - Clinical cancer research : an official journal of the American Association for Cancer Research JID - 9502500 RN - 0 (Hypoglycemic Agents) RN - 0 (Multiprotein Complexes) RN - 0 (Proteins) RN - 0 (Receptors, G-Protein-Coupled) RN - 0 (Transcription Factors) RN - 9100L32L2N (Metformin) RN - EC 2.7.10.1 (Receptor, IGF Type 1) RN - EC 2.7.10.1 (Receptor, Insulin) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Animals MH - Clinical Trials as Topic MH - Diabetes Mellitus, Type 2/drug therapy/pathology/physiopathology MH - Humans MH - Hypoglycemic Agents/pharmacology/therapeutic use MH - Mechanistic Target of Rapamycin Complex 1 MH - Metformin/*pharmacology/therapeutic use MH - Models, Biological MH - Multiprotein Complexes MH - Pancreatic Neoplasms/drug therapy/pathology/physiopathology MH - Proteins MH - Receptor Cross-Talk/*drug effects MH - Receptor, IGF Type 1/*physiology MH - Receptor, Insulin/*physiology MH - Receptors, G-Protein-Coupled/*physiology MH - Signal Transduction/drug effects MH - TOR Serine-Threonine Kinases MH - Transcription Factors/physiology PMC - PMC2862089 MID - NIHMS182856 EDAT- 2010/04/15 06:00 MHDA- 2010/08/21 06:00 PMCR- 2011/05/01 CRDT- 2010/04/15 06:00 PHST- 2010/04/15 06:00 [entrez] PHST- 2010/04/15 06:00 [pubmed] PHST- 2010/08/21 06:00 [medline] PHST- 2011/05/01 00:00 [pmc-release] AID - 1078-0432.CCR-09-2229 [pii] AID - 10.1158/1078-0432.CCR-09-2229 [doi] PST - ppublish SO - Clin Cancer Res. 2010 May 1;16(9):2505-11. doi: 10.1158/1078-0432.CCR-09-2229. Epub 2010 Apr 13.