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Suppression of survivin phosphorylation on Thr34 by flavopiridol enhances tumor cell apoptosis

Nathan R Wall1, Daniel S O'Connor, Janet Plescia

  • 1Department of Cancer Biology and Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.

Cancer Research
|January 9, 2003
PubMed

Insights

Survivin phosphorylation on Thr(34) is crucial for its expression in cancer cells. Inhibiting this phosphorylation enhances cancer cell apoptosis and suppresses tumor growth without toxicity.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Survivin, an inhibitor of apoptosis protein, is upregulated in many cancers, promoting tumor cell survival and proliferation.
  • Survivin's role in cancer progression and resistance to therapy necessitates understanding its regulatory mechanisms.

Purpose of the Study:

  • To investigate the role of survivin phosphorylation at Thr(34) in regulating survivin levels and its impact on cancer cell apoptosis and tumor growth.
  • To determine if targeting survivin phosphorylation can be a therapeutic strategy against cancer.

Main Methods:

  • Exposure of breast (MCF-7) and cervical (HeLa) cancer cells to anticancer agents (Adriamycin, Taxol, UVB) and flavopiridol.
  • Analysis of survivin expression, mRNA levels, and phosphorylation status.
  • Assessment of survivin Thr(34)-->Ala mutant stability and its effect on apoptosis and tumor growth in vivo.

Main Results:

  • Anticancer agents increased survivin expression without altering mRNA levels, suggesting post-transcriptional regulation.
  • Inhibition of Thr(34) phosphorylation by flavopiridol led to decreased survivin levels and accelerated clearance of a non-phosphorylatable mutant.
  • Ablation of Thr(34) phosphorylation enhanced anticancer agent-induced apoptosis, independent of p53, and suppressed tumor growth in a xenograft model.

Conclusions:

  • Thr(34) phosphorylation is critical for maintaining survivin levels in tumor cells.
  • Targeting survivin phosphorylation, specifically by inhibiting p34(cdc2) kinase activity, can overcome the survivin-mediated apoptosis evasion and suppress tumor growth.

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