Effects of metformin on cell growth and AMPK activity in pituitary adenoma cell cultures, focusing on the interaction with adenylyl cyclase activating signals

Mol Cell Endocrinol. 2018 Jul 15;470:60-74. doi: 10.1016/j.mce.2017.09.030. Epub 2017 Sep 27.

Abstract

For a few years we have been investigating AMP-activated protein kinase (AMPK) as a target for drug therapy of GH-secreting pituitary adenomas. Aim of this study was to investigate the direct effects of metformin, which causes AMPK activation in different cell types, on rat pituitary adenoma cell growth and on related cell signalling pathways. Our results suggest that metformin can exert a growth-inhibitory activity in rat pituitary tumor cells mediated by AMPK activation, although multiple mechanisms are most likely involved. Membrane proteins, including growth factor receptors, are valuable targets of AMPK. The inhibition of the mTOR-p70S6 kinase signalling pathway plays a role in the suppressive effect of metformin on pituitary tumor cell growth. Metformin did not affect the MTT reduction activity in energetic stress conditions. Finally, metformin was still able to induce AMPK activation and to inhibit cell growth in cells treated with forskolin and in transfected cells overexpressing GHRH-receptor and treated with GHRH. Hence, adenylyl cyclase over-activation does not account for the lack of response of some human pituitary tumors to AMPK-activating compounds in vitro.

Keywords: AMP-activated protein kinase; AMPK substrates; GHRH; Metformin; S6 ribosomal protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Adenylate Kinase / metabolism
  • Adenylyl Cyclases / metabolism*
  • Aminoimidazole Carboxamide / analogs & derivatives
  • Aminoimidazole Carboxamide / pharmacology
  • Animals
  • Apoptosis / drug effects
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cyclic AMP / metabolism
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Epidermal Growth Factor / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Growth Hormone-Releasing Hormone / metabolism
  • Humans
  • Metformin / pharmacology*
  • Phosphorylation / drug effects
  • Pituitary Neoplasms / enzymology*
  • Pituitary Neoplasms / pathology*
  • Rats
  • Ribonucleotides / pharmacology
  • Ribosomal Protein S6 / metabolism
  • Signal Transduction*
  • Stress, Physiological / drug effects
  • Tumor Cells, Cultured

Substances

  • Cyclic AMP Response Element-Binding Protein
  • Ribonucleotides
  • Ribosomal Protein S6
  • Aminoimidazole Carboxamide
  • Epidermal Growth Factor
  • Growth Hormone-Releasing Hormone
  • Metformin
  • Cyclic AMP
  • Extracellular Signal-Regulated MAP Kinases
  • AMP-Activated Protein Kinases
  • Adenylate Kinase
  • Adenylyl Cyclases
  • AICA ribonucleotide