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Netrin-1 Induces Apoptosis in Human Cervical Tumor Cells via the TAp73 Tumor Suppressor

¹ Institut National de la Sante et de la Recherche Medicale U673 Molecular and Clinical Oncology of Solid Tumors and Institut National de la Sante et de la Recherche Medicale U893; Université Pierre et Marie Curie-Paris 6, Faculté de Médecine, Hôpital Saint-Antoine, Paris, France; ² Laboratory of Experimental Cancerology and ³ Department of Medical Oncology, Gent University Hospital, Gent, Belgium; and ⁴ Medical Research Council, Toxicology Unit, Leicester University, Leicester, United Kingdom

Requests for reprints: Christian Gespach, Institut National de la Sante et de la Recherche Medicale, U673-U893, Hôpital Saint-Antoine, 75571 Paris Cedex 12, France. Phone: 33-1-43453477; Fax: 33-1-49384694; E-mail: christian.gespach{at}inserm.fr.

Key Words: DCC • cisplatin • Bcl-2/Bax • caspase-3 • p73 ubiquitination and silencing • abl • Itch • Yap-1

Netrins and their receptors deleted in colon cancer (DCC), neogenin, UNC5, and integrins are involved in axon guidance, epithelial morphogenesis, vascular pattering, cancer cell survival, invasion, tumor angiogenesis, and metastasis. Here, we considered the possible contribution of the p53-related apoptosis mediators p63 and p73 in the mechanisms underlying the antagonism between netrin-1 and DCC at the cell death control. We have showed that ectopic expression and external addition of netrin-1 in HeLa and HEK-293 cells with inactive p53 lead to impaired cell viability and induction of apoptosis. These responses were associated with up-regulation of the proapoptotic protein TAp73, decreased Bcl-2/Bax ratio, and caspase-3 cleavage, with no change in protein levels of the antiapoptotic NH₂-terminal–truncated Np73 isoform, p73 adapter Yap-1 and p73 E3 ubiquitin ligase Itch, and p63, as well as the transcripts encoding p63, TAp73, and Np73. However, the proteasome inhibitor MG132 potentiated, while DCC counteracted, netrin-1–induced TAp73. Consistently, netrin-1 expression correlated with stabilization of the TAp73 protein and lower levels of TAp73 ubiquitination that was conversely enhanced by DCC, in a netrin-dependent manner. Our data indicate that netrin-1 selectively up-regulates TAp73 by preventing its ubiquitination and degradation. Targeted repression of p73 by shRNA reversed TAp73 and the apoptosis induced by netrin-1, and exacerbated the growth of HeLa tumor xenografts. Apoptosis induced by cisplatin was markedly enhanced in netrin-1 or DCC-expressing cells. Collectively, our data reveal that the transcriptionally active TAp73 tumor suppressor is implicated in the apoptosis induced by netrin-1 in a p53-independent and DCC/ubiquitin-proteasome dependent manner. [Cancer Res 2008;68(20):8231–9]

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