PT  - JOURNAL ARTICLE
AU  - Zhao, Carolyn Ying
AU  - Szekely, Laszlo
AU  - Bao, Wenjie
AU  - Selivanova, Galina
TI  - Rescue of p53 Function by Small-Molecule RITA in Cervical Carcinoma by Blocking E6-Mediated Degradation
AID  - 10.1158/0008-5472.CAN-09-2787
DP  - 2010 Apr 15
TA  - Cancer Research
PG  - 3372--3381
VI  - 70
IP  - 8
4099  - http://cancerres.aacrjournals.org/content/70/8/3372.short
4100  - http://cancerres.aacrjournals.org/content/70/8/3372.full
SO  - Cancer Res2010 Apr 15; 70
AB  - 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. Cancer Res; 70(8); 3372–81. ©2010 AACR.©2010 American Association for Cancer Research.