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AMP-activated kinase (AMPK) regulates activity of HER2 and EGFR in breast cancer

Teraneh Z Jhaveri1, Juhyung Woo1, Xiaobin Shang1

  • 1Departments of Pathology and Oncology and The Sydney Kimmel Cancer Center, The Johns Hopkins School of Medicine, Baltimore, MD, USA.

Oncotarget
|July 6, 2015
PubMed

Insights

AMP-activated Protein Kinase (AMPK) activation inhibits growth in HER2-amplified breast cancers by suppressing HER2/EGFR signaling. This suggests AMPK activation may offer a novel therapeutic strategy for these aggressive cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • AMP-activated Protein Kinase (AMPK) activity is known to inhibit the growth of various cancer types.
  • HER2 and EGFR are receptor tyrosine kinases often overexpressed in aggressive breast cancers, driving tumor progression.

Purpose of the Study:

  • To investigate the effects of AMPK activation on breast cancer cell signaling and survival, particularly in HER2/EGFR-amplified cells.
  • To elucidate the molecular mechanisms by which AMPK influences HER2 and EGFR activity.

Main Methods:

  • Utilized AICAR, a pharmacological AMPK activator, and transfected constitutively active AMPKα in breast cancer cell lines.
  • Performed cell viability assays, Western blotting for protein phosphorylation, co-immunoprecipitation, and in vitro kinase assays.
  • Analyzed dose- and time-dependent effects of AICAR on HER2/EGFR signaling pathways.

Main Results:

  • Breast cancer cells overexpressing HER2/EGFR were 2- to 5-fold more sensitive to AICAR-induced cytotoxicity.
  • AICAR treatment and AMPKα transfection led to dose- and time-dependent inhibition of HER2 and EGFR phosphorylation and downstream signaling.
  • AMPK was found to interact with HER2, and HER2/EGFR contain potential AMPK phosphorylation sites, suggesting direct regulation.

Conclusions:

  • AMPK activation suppresses HER2 and EGFR activity in HER2-amplified breast cancer cells.
  • AMPK's interaction with and potential phosphorylation of HER2/EGFR mediate its anti-proliferative effects.
  • Targeting AMPK activation represents a potential therapeutic strategy for HER2-amplified breast cancers.
Keywords:
AMP-activated protein kinase (AMPK)EGFRHER2cancer cell metabolismcancer therapy

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