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S6 kinase 2 promotes breast cancer cell survival via Akt

Savitha Sridharan1, Alakananda Basu

  • 1Department of Molecular Biology & Immunology, University of North Texas Health Science Center, Fort Worth, Texas, USA.

Cancer Research
|March 24, 2011
PubMed

Insights

Targeting S6K2, a ribosomal protein kinase, enhances cancer cell apoptosis by modulating Akt activation and p53 signaling. This study reveals distinct roles for S6K1 and S6K2 in cell survival, suggesting S6K2 as a potential cancer therapy target.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • The 40S ribosomal protein S6 kinase (S6K) pathway, downstream of mTOR, is crucial for cell proliferation, translation, and survival, making it a cancer therapy target.
  • While mTOR inhibitors show limited success, the specific roles of S6K homologues, particularly S6K2, in regulating cell survival and Akt activation remain largely uncharacterized.
  • A negative feedback loop exists where S6K1 inhibition can activate Akt, complicating therapeutic strategies.

Purpose of the Study:

  • To investigate the distinct functions of S6K2 compared to S6K1 in regulating Akt activation and mediating apoptosis.
  • To elucidate the molecular mechanisms by which S6K2 influences cell survival pathways, including Akt, p53, and Bid.
  • To evaluate the potential of targeting S6K2 as a therapeutic strategy for cancer treatment.

Main Methods:

  • Utilized siRNA to selectively knockdown S6K1 and S6K2 in cancer cells.
  • Assessed apoptosis induction via TNF-α and TRAIL (TNF-related apoptosis-inducing ligand) signaling.
  • Analyzed Akt phosphorylation, p53 levels, and Bid expression using Western blotting and other molecular techniques.
  • Employed ectopic expression of constitutively active Akt and siRNA-mediated p53 and Bid silencing to dissect signaling pathways.

Main Results:

  • Knockdown of S6K2 significantly increased TNF-α and TRAIL-mediated apoptosis, while S6K1 silencing had a modest effect.
  • S6K2 depletion led to decreased basal and TNF-induced Akt phosphorylation, contrasting with S6K1.
  • S6K2 deficiency resulted in increased p53 levels, subsequent Bid downregulation, and enhanced apoptosis, which was abrogated by Bid silencing.
  • Restoration of Akt activity rescued cell survival in S6K2-depleted cells.

Conclusions:

  • S6K1 and S6K2 exhibit distinct and opposing roles in regulating Akt activation and cell survival.
  • S6K2 functions as a negative regulator of apoptosis, partly through its influence on the Akt/p53/Bid axis.
  • Targeting S6K2 presents a promising and novel therapeutic strategy for enhancing cancer cell apoptosis and treating malignancies.

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