title: 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.
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.
authors.affiliation: 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
authors.forename: Enrique
authors.initials: E
authors.lastname: Rozengurt
authors.forename: James
authors.initials: J
authors.lastname: Sinnett-Smith
authors.forename: Krisztina
authors.initials: K
authors.lastname: Kisfalvi
mesh_terms: 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
chemical_list: 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
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