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Degradation of AMPK by a cancer-specific ubiquitin ligase

Carlos T Pineda1, Saumya Ramanathan1, Klementina Fon Tacer1

  • 1Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Cell
|February 14, 2015
PubMed

Insights

Cancer cells suppress AMP-activated protein kinase (AMPK) by hijacking a germline mechanism involving MAGE-A3/6-TRIM28. This leads to AMPKα1 degradation, promoting cancer growth and sensitivity to AMPK-targeting drugs.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Metabolism

Background:

  • AMP-activated protein kinase (AMPK) is a critical regulator of cellular energy homeostasis, suppressing anabolic processes and promoting catabolism during metabolic stress.
  • Cancer cells can evade AMPK's growth-restrictive functions through various mechanisms, including mutations in upstream regulatory kinases.
  • MAGE-A3 and MAGE-A6 are proteins typically restricted to the male germline but are frequently reactivated in human cancers, where they are essential for tumor cell viability.

Purpose of the Study:

  • To elucidate a novel mechanism by which cancer cells suppress AMPK activity.
  • To identify the specific targets and functions of the MAGE-A3/6-TRIM28 ubiquitin ligase complex in cancer.
  • To understand the implications of AMPK suppression for cancer progression and therapeutic strategies.

Main Methods:

  • Utilized screening assays to identify targets of the MAGE-A3/6-TRIM28 ubiquitin ligase complex.
  • Performed ubiquitination assays to confirm direct targeting of AMPKα1 by MAGE-A3/6-TRIM28.
  • Assessed the functional consequences of AMPKα1 degradation on autophagy, mTOR signaling, and cellular response to AMPK agonists like metformin.

Main Results:

  • Identified MAGE-A3/6-TRIM28 as a ubiquitin ligase that specifically targets and degrades AMPKα1.
  • Demonstrated that MAGE-A3/6-mediated AMPKα1 degradation leads to the inhibition of autophagy.
  • Showed that suppression of AMPK results in mTOR pathway activation and increased sensitivity of cancer cells to AMPK agonists.

Conclusions:

  • A widespread mechanism in cancer involves the suppression of AMPK through MAGE-A3/6-TRIM28-mediated ubiquitination and degradation of AMPKα1.
  • This hijacked germline mechanism contributes to cancer cell viability by inhibiting tumor-suppressive pathways like autophagy.
  • Targeting this MAGE-A3/6-TRIM28-AMPK axis may represent a promising therapeutic strategy for cancers exhibiting MAGE-A3/6 re-expression.

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