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HDM2 regulation by AURKA promotes cell survival in gastric cancer

Vikas Sehdev1, Ahmed Katsha, Janet Arras

  • 1Authors' Affiliations: Departments of Surgery and Cancer Biology, Vanderbilt University Medical Center; Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee; Translational Medicine, Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts; and Department of Pharmacology, Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, New York.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|November 19, 2013
PubMed
Abstract

Insights

Aurora kinase A (AURKA) promotes gastric cancer growth by regulating HDM2, which inhibits tumor suppressor P53. Inhibiting AURKA decreases HDM2, reactivates P53, and reduces tumor survival.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • P53 (tumor protein 53) is a critical tumor suppressor.
  • Suppression of P53 function leads to poor cancer therapy response.
  • Aurora kinase A (AURKA) and human double minute 2 (HDM2) are negative regulators of P53.

Purpose of the Study:

  • To investigate the role of AURKA in regulating HDM2.
  • To determine the effects of AURKA-HDM2 interaction on P53 apoptotic function in gastric cancer.

Main Methods:

  • Utilized gastric cancer cell models with AURKA overexpression or knockdown.
  • Investigated AURKA's regulation of HDM2, cell survival, and P53 activity.
  • Performed co-immunoprecipitation and in vitro kinase assays.
  • Used the small-molecule inhibitor alisertib to target AURKA.

Main Results:

  • AURKA overexpression increased HDM2 protein levels; AURKA knockdown decreased HDM2.
  • AURKA directly interacts with and phosphorylates HDM2.
  • AURKA-mediated HDM2 activation led to P53 ubiquitination and reduced cisplatin-induced P53 activity.
  • Alisertib treatment decreased HDM2, increased P53 activity, and reduced tumor growth.
  • Gastric cancer tissues showed significant overexpression of AURKA and HDM2.

Conclusions:

  • AURKA promotes gastric cancer growth and survival by enhancing HDM2-mediated P53 inhibition.
  • Targeting AURKA represents a potential therapeutic strategy for gastric cancer.

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