Rescue of p53 function by small-molecule RITA in cervical carcinoma by blocking E6-mediated degradation.
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.
Zhao
Carolyn Ying
CY
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
Szekely
Laszlo
L
Bao
Wenjie
W
Selivanova
Galina
G
D017209:Apoptosis; D016203:CDC2 Protein Kinase / Q000737:chemistry; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism*; D049109:Cell Proliferation; D002470:Cell Survival; D056744:Cyclin B1 / Q000378:metabolism; D005260:Female; D005663:Furans / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025801:Ubiquitin / Q000737:chemistry; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D020687:cdc25 Phosphatases / Q000737:chemistry
D056744:Cyclin B1; C068651:E6 protein, Human papillomavirus type 16; D005663:Furans; C118989:NSC 652287; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; D016203:CDC2 Protein Kinase; D020687:cdc25 Phosphatases