A novel insight into the anticancer mechanism of metformin in pancreatic neuroendocrine tumor cells

Mol Cell Endocrinol. 2020 Jun 1:509:110803. doi: 10.1016/j.mce.2020.110803. Epub 2020 Apr 3.

Abstract

The antidiabetic drug metformin displays anticancer properties in several neoplasms. In pituitary NETs, aryl hydrocarbon receptor-interacting protein (AIP) is up-regulated by the somatostatin analog octreotide. Metformin inhibited QGP-1 cell proliferation in a dose- and time-dependent manner, at concentrations similar to those achievable in treated patients (-31 ± 12%, p < 0.05 vs basal at 100 μM). Moreover, metformin decreased pancreatic neuroendocrine tumors (PAN-NETs) cell proliferation (-62 ± 15%, p < 0.0001 vs basal at 10 mM), without any additive effect when combined with octreotide. Both octreotide and metformin induced AIP up-regulation. AIP silencing abolished the reduction of mTOR phosphorylation induced by metformin and octreotide. Moreover, metformin decreased HSP70, increased Zac1 and AhR expression; these effects were abolished in AIP silenced QGP-1 cells. In conclusion, metformin acts as an anticancer agent in PAN-NET cells, its activity is mediated by AIP and its interacting proteins. These findings provide a novel insight into the antitumorigenic mechanism of metformin.

Keywords: AIP; Metformin; Octreotide; Pancreatic neuroendocrine tumors; mTOR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Apoptosis / drug effects
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Female
  • Gene Silencing / drug effects
  • HSP70 Heat-Shock Proteins / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Male
  • Metformin / pharmacology
  • Metformin / therapeutic use*
  • Middle Aged
  • Models, Biological
  • Neuroendocrine Tumors / drug therapy*
  • Neuroendocrine Tumors / pathology
  • Octreotide / pharmacology
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / pathology
  • Phosphorylation / drug effects
  • Protein Binding
  • Receptors, Aryl Hydrocarbon / metabolism
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / metabolism
  • Transcription Factors / metabolism
  • Tumor Stem Cell Assay
  • Tumor Suppressor Proteins / metabolism

Substances

  • Antineoplastic Agents
  • Cell Cycle Proteins
  • HSP70 Heat-Shock Proteins
  • Intracellular Signaling Peptides and Proteins
  • PLAGL1 protein, human
  • Receptors, Aryl Hydrocarbon
  • Transcription Factors
  • Tumor Suppressor Proteins
  • aryl hydrocarbon receptor-interacting protein
  • Metformin
  • TOR Serine-Threonine Kinases
  • Octreotide