Gain-of-function mutant p53 promotes cell growth and cancer cell metabolism via inhibition of AMPK activation

Mol Cell. 2014 Jun 19;54(6):960-74. doi: 10.1016/j.molcel.2014.04.024. Epub 2014 May 22.

Abstract

Many mutant p53 proteins (mutp53s) exert oncogenic gain-of-function (GOF) properties, but the mechanisms mediating these functions remain poorly defined. We show here that GOF mutp53s inhibit AMP-activated protein kinase (AMPK) signaling in head and neck cancer cells. Conversely, downregulation of GOF mutp53s enhances AMPK activation under energy stress, decreasing the activity of the anabolic factors acetyl-CoA carboxylase and ribosomal protein S6 and inhibiting aerobic glycolytic potential and invasive cell growth. Under conditions of energy stress, GOF mutp53s, but not wild-type p53, preferentially bind to the AMPKα subunit and inhibit AMPK activation. Given the importance of AMPK as an energy sensor and tumor suppressor that inhibits anabolic metabolism, our findings reveal that direct inhibition of AMPK activation is an important mechanism through which mutp53s can gain oncogenic function.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / antagonists & inhibitors
  • AMP-Activated Protein Kinases / metabolism*
  • Acetyl-CoA Carboxylase / metabolism
  • Animals
  • Antimetabolites, Antineoplastic / pharmacology
  • Carcinoma, Squamous Cell / genetics*
  • Cell Movement / genetics
  • Cell Proliferation
  • Energy Metabolism / genetics*
  • Enzyme Activation / genetics
  • Fluorouracil / pharmacology
  • Head and Neck Neoplasms / genetics*
  • Humans
  • Mice
  • Mice, Nude
  • Neoplasm Invasiveness / genetics
  • Neoplasm Transplantation
  • Protein Binding / genetics
  • RNA Interference
  • RNA, Small Interfering
  • Ribosomal Protein S6 / metabolism
  • Signal Transduction / genetics
  • Spheroids, Cellular / cytology
  • Squamous Cell Carcinoma of Head and Neck
  • Transplantation, Heterologous
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Antimetabolites, Antineoplastic
  • RNA, Small Interfering
  • Ribosomal Protein S6
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • AMP-Activated Protein Kinases
  • Acetyl-CoA Carboxylase
  • Fluorouracil