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Apollon gene silencing induces apoptosis in breast cancer cells through p53 stabilisation and caspase-3 activation

By A Lopergolo, M Pennati, P Gandellini, N I Orlotti, P Poma, M G Daidone, M Folini and N Zaffaroni

Abstract

We analysed the effects of small interfering RNA (siRNA)-mediated silencing of Apollon, a member of the inhibitors of apoptosis protein family, on the proliferative potential and ability of human breast cancer cell lines to undergo apoptosis. In wild-type p53 ZR75.1 cells, Apollon knockdown resulted in a marked, time-dependent decline of cell growth and an increased rate of apoptosis, which was associated with p53 stabilisation and activation of the mitochondrial-dependent apoptotic pathway. Pre-incubation of cells with a p53-specific siRNA resulted in a partial rescue of cell growth inhibition, as well as in a marked reduction of the apoptotic response, indicating p53 as a major player in cell growth impairment consequent on Apollon silencing. Apollon knockdown induced consistently less pronounced anti-proliferative and pro-apoptotic effects in mutant p53 MDA-MB-231 cells than in ZR75.1 cells. Furthermore, the activation of caspase-3 seemed to be essential for the induction of apoptosis after Apollon knockdown, as the Apollon-specific siRNA had no effect on the viability of caspase-3-deficient, wild-type p53 MCF-7 cells or the ZR75.1 cells after RNA interference-mediated caspase-3 silencing. Our results indicate that p53 stabilisation and caspase-3 activation concur to determine the apoptotic response mediated by Apollon knockdown in breast cancer cells, and suggest Apollon to be a potential new therapeutic target for this malignancy

Topics: Translational Therapeutics
Publisher: Nature Publishing Group
OAI identifier: oai:pubmedcentral.nih.gov:2653776
Provided by: PubMed Central
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    Citations

    1. (2004). Dual role of BRUCE as an antiapoptotic IAP and a chimeric E2/E3 ubiquitin ligase.

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