MicroRNA-451 regulates LKB1/AMPK signaling and allows adaptation to metabolic stress in glioma cells

Mol Cell. 2010 Mar 12;37(5):620-32. doi: 10.1016/j.molcel.2010.02.018.

Abstract

To sustain tumor growth, cancer cells must be able to adapt to fluctuations in energy availability. We have identified a single microRNA that controls glioma cell proliferation, migration, and responsiveness to glucose deprivation. Abundant glucose allows relatively high miR-451 expression, promoting cell growth. In low glucose, miR-451 levels decrease, slowing proliferation but enhancing migration and survival. This allows cells to survive metabolic stress and seek out favorable growth conditions. In glioblastoma patients, elevated miR-451 is associated with shorter survival. The effects of miR-451 are mediated by LKB1, which it represses through targeting its binding partner, CAB39 (MO25 alpha). Overexpression of miR-451 sensitized cells to glucose deprivation, suggesting that its downregulation is necessary for robust activation of LKB1 in response to metabolic stress. Thus, miR-451 is a regulator of the LKB1/AMPK pathway, and this may represent a fundamental mechanism that contributes to cellular adaptation in response to altered energy availability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / metabolism*
  • Adaptation, Physiological
  • Animals
  • Brain Neoplasms / enzymology*
  • Brain Neoplasms / genetics
  • Brain Neoplasms / mortality
  • Brain Neoplasms / pathology
  • COS Cells
  • Calcium-Binding Proteins / metabolism
  • Cell Movement
  • Cell Proliferation
  • Cell Survival
  • Chlorocebus aethiops
  • Enzyme Activation
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Neoplastic
  • Glioblastoma / enzymology*
  • Glioblastoma / genetics
  • Glioblastoma / mortality
  • Glioblastoma / pathology
  • Glucose / deficiency
  • HeLa Cells
  • Humans
  • MicroRNAs / metabolism*
  • Prognosis
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Signal Transduction* / genetics
  • Stress, Physiological* / genetics
  • Time Factors
  • Transfection

Substances

  • CAB39 protein, human
  • Calcium-Binding Proteins
  • MIRN451 microRNA, human
  • MicroRNAs
  • STK11 protein, human
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases
  • Glucose