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Netrin-1 induces apoptosis in human cervical tumor cells via the TAp73alpha tumor suppressor

Jean-Pierre Roperch1, Karima El Ouadrani, Ann Hendrix

  • 1Institut National de la Sante, Recherche Medicale U673 Molecular and Clinical Oncology of Solid Tumors, Université Pierre et Marie Curie-Paris 6, Hôpital Saint-Antoine, Paris, France.

Cancer Research
|October 17, 2008
PubMed

Insights

Netrin-1 induces apoptosis by stabilizing the TAp73alpha protein, independent of p53. This mechanism, involving DCC and the ubiquitin-proteasome system, offers a potential therapeutic target for cancer, as inhibiting p73 reversed netrin-1

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Cancer Therapeutics

Background:

  • Netrins and their receptors (DCC, neogenin, UNC5, integrins) are implicated in cancer progression, affecting cell survival, invasion, angiogenesis, and metastasis.
  • The p53-related apoptosis mediators p63 and p73 are crucial in cell death control, but their role in netrin-1/DCC signaling remains unclear.
  • Netrin-1 and DCC antagonism is linked to cell death mechanisms, prompting investigation into p63 and p73 involvement.

Purpose of the Study:

  • To investigate the role of p63 and p73 in the antagonistic relationship between netrin-1 and DCC in controlling cell death.
  • To elucidate the molecular mechanisms by which netrin-1 influences p73 isoforms and apoptosis.
  • To assess the therapeutic potential of targeting the netrin-1/p73 pathway in cancer.

Main Methods:

  • Ectopic expression and external addition of netrin-1 in HeLa and HEK-293 cells with inactive p53.
  • Analysis of apoptosis markers, including TAp73alpha, DeltaNp73alpha, Bcl-2/Bax ratio, and caspase-3 cleavage.
  • Investigation of protein ubiquitination and degradation using proteasome inhibitors (MG132) and DCC expression.
  • Tumor xenograft studies with targeted repression of p73alpha using shRNA.
  • Assessment of apoptosis induction by netrin-1, DCC, and cisplatin.

Main Results:

  • Netrin-1 induced apoptosis and impaired cell viability in p53-inactive cells, associated with TAp73alpha upregulation and decreased Bcl-2/Bax ratio.
  • Netrin-1 selectively stabilized TAp73alpha by preventing its ubiquitination and degradation, a process counteracted by DCC.
  • Targeted repression of p73alpha reversed netrin-1-induced apoptosis and exacerbated tumor growth, while netrin-1 or DCC enhanced cisplatin-induced apoptosis.

Conclusions:

  • Netrin-1 induces apoptosis in a p53-independent manner, mediated by the stabilization of the proapoptotic TAp73alpha isoform via the DCC/ubiquitin-proteasome pathway.
  • The transcriptionally active TAp73alpha tumor suppressor plays a critical role in netrin-1-induced apoptosis.
  • This pathway represents a potential therapeutic strategy for enhancing cancer cell apoptosis.

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