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Cancer Res. 2010 Apr 15;70(8):3372-81. doi: 10.1158/0008-5472.CAN-09-2787.

Rescue of p53 function by small-molecule RITA in cervical carcinoma by blocking E6-mediated degradation.

Author information

1
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.

Abstract

Proteasomal degradation of p53 by human papilloma virus (HPV) E6 oncoprotein plays a pivotal role in the survival of cervical carcinoma cells. Abrogation of HPV-E6-dependent p53 destruction can therefore be a good strategy to combat cervical carcinomas. Here, we show that a small-molecule reactivation of p53 and induction of tumor cell apoptosis (RITA) is able to induce the accumulation of p53 and rescue its tumor suppressor function in cells containing high-risk HPV16 and HPV18 by inhibiting HPV-E6-mediated proteasomal degradation. RITA blocks p53 ubiquitination by preventing p53 interaction with E6-associated protein, required for HPV-E6-mediated degradation. RITA activates the transcription of proapoptotic p53 targets Noxa, PUMA, and BAX, and repressed the expression of pro-proliferative factors CyclinB1, CDC2, and CDC25C, resulting in p53-dependent apoptosis and cell cycle arrest. Importantly, RITA showed substantial suppression of cervical carcinoma xenografts in vivo. These results provide a proof of principle for the treatment of cervical cancer in a p53-dependent manner by using small molecules that target p53.

PMID:
20395210
DOI:
10.1158/0008-5472.CAN-09-2787
[Indexed for MEDLINE]
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