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Hsp72 mediates TAp73α anti-apoptotic effects in small cell lung carcinoma cells

Ulrika Nyman1, Naveen Reddy Muppani, Boris Zhivotovsky

  • 1Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden.

Journal of Cellular and Molecular Medicine
|September 3, 2010
PubMed

Insights

The transcription factor TAp73α promotes cancer cell survival by regulating Hsp72 expression, conferring resistance to apoptosis. TAp73β counteracts this effect, highlighting a potential oncogenic role for TAp73α in tumors.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cellular Biology

Background:

  • The p53 family member p73 regulates cell cycle and apoptosis.
  • The P73 gene generates multiple isoforms, including TAp73α, which is upregulated in tumors.
  • TAp73α confers resistance to drug-induced apoptosis in small cell lung carcinoma (SCLC) cells, but its mechanism is unclear.

Purpose of the Study:

  • To elucidate the mechanism by which TAp73α confers a pro-survival effect in SCLC cells.
  • To investigate the role of inducible Hsp72 (HSPA1A) in TAp73α-mediated apoptosis resistance.
  • To determine the influence of TAp73β on TAp73α's anti-apoptotic function.

Main Methods:

  • Investigated the regulation of inducible Hsp72 expression by TAp73α and TAp73β.
  • Utilized antisense knockdown of Hsp72 to assess its role in TAp73α's survival effects.
  • Monitored Bax activation, mitochondrial membrane potential, and lysosomal membrane permeabilization.

Main Results:

  • TAp73α, but not TAp73β, specifically regulates inducible Hsp72 expression.
  • Hsp72 is essential for TAp73α's anti-apoptotic effects; Hsp72 knockdown abolished resistance to etoposide-induced apoptosis in SCLC cells.
  • Hsp72 depletion restored Bax activation, mitochondrial dysfunction, and lysosomal damage in SCLC cells, even with TAp73α present.
  • TAp73β inhibited TAp73α's anti-apoptotic function by preventing Hsp72 induction.

Conclusions:

  • TAp73α promotes SCLC cell survival by inducing Hsp72, thereby inhibiting apoptosis.
  • TAp73β antagonizes TAp73α's pro-survival role, suggesting a regulatory balance.
  • These findings support a potential oncogenic role for TAp73α and clarify its anti-apoptotic mechanism involving Hsp72.

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