ORIGINAL ARTICLE

Cell Research (2008): 664-676
© 2008 IBCB, SIBS, CAS All rights reserved 1001-0602/06 $ 30.00
www.nature.com/cr

Roscovitine sensitizes breast cancer cells to TRAIL-induced apoptosis through a pleiotropic mechanism

Gustavo Ortiz-Ferrón¹, Rosario Yerbes¹, Adriana Eramo², Ana I López-Pérez¹, Ruggero De Maria² and Abelardo López-Rivas¹

Correspondence: Abelardo López-Rivas Tel: +34-95-446-7997; Fax: +34-95-446-1664 E-mail: abelardo.lopez@cabimer.es

Download as printable (PDF) file Full Text (html)file Search Medline for articles by: Gustavo Ortiz-Ferrón

The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL/APO2L) is a member of the TNF gene superfamily that induces apoptosis upon engagement of cognate death receptors. While TRAIL is relatively non-toxic to normal cells, it selectively induces apoptosis in many transformed cells. Nevertheless, breast tumor cells are particularly resistant to the effects of TRAIL. Here we report that, in combination with the cyclin-dependent kinase inhibitor roscovitine, exposure to TRAIL induced marked apoptosis in the majority of TRAIL-resistant breast cancer cell lines examined. Roscovitine facilitated TRAIL death-inducing signaling complex formation and the activation of caspase-8. The cFLIP_L and cFLIP_S FLICE-inhibitory proteins were significantly down-regulated following exposure to roscovitine and, indeed, the knockdown of cFLIP isoforms by siRNA sensitized breast tumor cells to TRAIL-induced apoptosis. In addition, we demonstrate that roscovitine strongly suppressed Mcl-1 expression and up-regulated E2F1 protein levels in breast tumor cells. Significantly, the silencing of Mcl-1 by siRNA sensitized breast tumor cells to TRAIL-induced apoptosis. Furthermore, the knockdown of E2F1 protein by siRNA reduced the sensitizing effect of roscovitine in TRAIL-induced apoptosis. In summary, our results reveal a pleitropic mechanism for the pro-apoptotic influence of roscovitine, highlighting its potential as an antitumor agent in breast cancer in combination with TRAIL.

Cell Research (2008) 18:664-676. doi: 10.1038/cr.2008.54; published online 06 May 2008

Keywords: apoptosis, roscovitine, CDK, TRAIL, DISC, FLIP, Mcl-1, E2F1