Activation of adenosine monophosphate activated protein kinase inhibits growth of multiple myeloma cells

Exp Cell Res. 2007 Oct 1;313(16):3592-603. doi: 10.1016/j.yexcr.2007.06.020. Epub 2007 Jul 4.

Abstract

The role of adenosine monophosphate activated protein kinase (AMPK) in regulating multiple myeloma (MM) cell growth is not yet clear. In this study, we show that the AMPK activators 5-aminoimidazole-4-carboxamide riboside (AICAr) and D942 inhibit cell growth in MM cell lines. AICAr also induced an S-phase cell cycle arrest in all four tested cell lines and led to phosphorylation and thus activation of AMPK. Furthermore, the inhibition of a nucleoside transporter by nitrobenzyl-thio-9-beta-d-ribofuranosylpurine (NBTI), inhibition of the adenosine kinase by iodotubericidine and inhibition of AMPK by AMPKI Compound C reversed AICAr effects, indicating that the cellular effects of AICAr were mediated by AMPK. Activation of AMPK inhibited basal extracellular signal-regulated kinase (ERK), mammalian target of rapamycin (mTOR) and P70S6 kinase (P70S6K) as well as AKT phosphorylation, and blocked IL-6, IGF-1, and HS-5 stromal cell conditioned medium-induced increase of cell growth. Troglitazone, which has previously been shown to activate AMPK, similarly inhibited MM cell growth, activated AMPK, and decreased ERK and P70S6K phosphorylation. Our results suggest that activation of AMPK inhibits MM cell growth despite stimulation with IL-6, IGF-1, or HS-5 stromal cell conditioned medium and represents a potential new target in the therapy of MM.

MeSH terms

  • AMP-Activated Protein Kinases
  • Aminoimidazole Carboxamide / analogs & derivatives
  • Aminoimidazole Carboxamide / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chromans / pharmacology
  • Culture Media, Conditioned
  • Enzyme Activation / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Humans
  • Insulin-Like Growth Factor I / pharmacology
  • Interleukin-6 / pharmacology
  • Multienzyme Complexes / metabolism*
  • Multiple Myeloma / enzymology*
  • Multiple Myeloma / pathology*
  • Phosphorylation / drug effects
  • Protein Kinases / metabolism
  • Protein-Serine-Threonine Kinases / metabolism*
  • Ribonucleotides / pharmacology
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • S Phase / drug effects
  • Signal Transduction / drug effects
  • Stromal Cells / drug effects
  • TOR Serine-Threonine Kinases
  • Thiazolidinediones / pharmacology
  • Troglitazone

Substances

  • Chromans
  • Culture Media, Conditioned
  • Interleukin-6
  • Multienzyme Complexes
  • Ribonucleotides
  • Thiazolidinediones
  • Aminoimidazole Carboxamide
  • Insulin-Like Growth Factor I
  • Protein Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Protein-Serine-Threonine Kinases
  • Ribosomal Protein S6 Kinases, 70-kDa
  • Extracellular Signal-Regulated MAP Kinases
  • AMP-Activated Protein Kinases
  • AICA ribonucleotide
  • Troglitazone