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

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.

• Authors: E Vitali, I Boemi, S Piccini, G Tarantola, V Smiroldo, E Lavezzi, T Brambilla, A Zerbi, C Carnaghi, G Mantovani, A Spada, A G Lania
• Journal: Molecular and cellular endocrinology (Mol Cell Endocrinol) Vol. 509 Pg. 110803 (06 01 2020) ISSN: 1872-8057 [Electronic] Ireland
• PMID: 32251713 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• 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

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (pharmacology, 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, therapeutic use)
• Middle Aged
• Models, Biological
• Neuroendocrine Tumors (drug therapy, pathology)
• Octreotide (pharmacology)
• Pancreatic Neoplasms (drug therapy, 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)