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AMPKα2 Regulates Bladder Cancer Growth through SKP2-Mediated Degradation of p27

Stavros Kopsiaftis1,2, Katie L Sullivan1,2, Isha Garg1,2

  • 1Center for Vascular Biology, University of Connecticut Health Center, Farmington Connecticut.

Molecular Cancer Research : MCR
|September 18, 2016
PubMed

Insights

AMP-activated protein kinase alpha 2 (AMPKα2) suppresses bladder cancer growth by regulating proliferation via mTOR and p27 protein levels. Loss of AMPKα2 promotes tumor development, indicating its potential as a therapeutic target.

Area of Science:

  • Cellular metabolism and cancer biology
  • Oncology and molecular mechanisms of tumorigenesis

Background:

  • AMP-activated protein kinase (AMPK) is a key metabolic regulator, often suppressed in cancers.
  • AMPK's role in bladder cancer progression and its specific isoforms require further elucidation.

Purpose of the Study:

  • To investigate the role of AMPK in regulating bladder cancer cell growth.
  • To determine the specific AMPK isoform involved in controlling proliferation and p27 protein levels.

Main Methods:

  • Treatment of bladder cancer cells (HTB2, HT1376) with an AMPK activator (AICAR).
  • Knockdown of AMPKα1 and AMPKα2 using shRNA in cell lines.
  • Analysis of proliferation, p27Kip1 (CDKN1B) and SKP2 protein levels.
  • Evaluation in xenograft and chemical carcinogen bladder cancer models.
  • Assessment of human primary bladder cancer specimens.

Main Results:

  • AICAR treatment reduced bladder cancer cell proliferation and increased p27Kip1 via mTOR.
  • AMPKα2 knockdown, but not AMPKα1, led to increased proliferation and decreased p27 protein.
  • Reduced p27 was dependent on SKP2, with high SKP2 levels observed upon AMPKα2 loss.
  • Loss of AMPKα2 in vivo resulted in larger tumors with reduced p27 and elevated SKP2.
  • Human bladder tumors showed low AMPKα2 and p27, and high SKP2 levels.

Conclusions:

  • AMPKα2 controls bladder cancer growth by suppressing proliferation through mTOR and inducing p27.
  • Loss of AMPKα2 function contributes to bladder cancer development.
  • AMPKα2 is a potential therapeutic target for bladder cancer treatment.

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