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

Clin Cancer Res. 2010 May 1;16(9):2505-11. doi: 10.1158/1078-0432.CCR-09-2229. Epub 2010 Apr 13.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Clinical Trials as Topic
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / pathology
  • Diabetes Mellitus, Type 2 / physiopathology
  • Humans
  • Hypoglycemic Agents / pharmacology
  • Hypoglycemic Agents / therapeutic use
  • Mechanistic Target of Rapamycin Complex 1
  • Metformin / pharmacology*
  • Metformin / therapeutic use
  • Models, Biological
  • Multiprotein Complexes
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / pathology
  • Pancreatic Neoplasms / physiopathology
  • Proteins
  • Receptor Cross-Talk / drug effects*
  • Receptor, IGF Type 1 / physiology*
  • Receptor, Insulin / physiology*
  • Receptors, G-Protein-Coupled / physiology*
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases
  • Transcription Factors / physiology

Substances

  • Hypoglycemic Agents
  • Multiprotein Complexes
  • Proteins
  • Receptors, G-Protein-Coupled
  • Transcription Factors
  • Metformin
  • Receptor, IGF Type 1
  • Receptor, Insulin
  • Mechanistic Target of Rapamycin Complex 1
  • TOR Serine-Threonine Kinases