Human papillomavirus type 16 E5 protein inhibits hydrogen-peroxide-induced apoptosis by stimulating ubiquitin-proteasome-mediated degradation of Bax in human cervical cancer cells.
To investigate the mechanism by which the human papillomavirus (HPV) E5 protein contributes to the carcinogenesis of uterine cervical cancer, we studied the effect of HPV E5 on apoptosis of cervical cancer cells and its underlying mechanism. Expression of HPV16 E5 protein inhibited hydrogen peroxide-induced apoptosis in C-33A cervical cancer cells. E5 decreased the expression of Bax protein, and exogenous expression of Bax abolished the anti-apoptotic effect of E5. Knockdown of E5 by small interfering RNA sensitized CaSki cervical cancer cells to hydrogen peroxide-induced apoptosis with concurrent increase in Bax expression. Transient expression of E5 significantly increased the degradation rate of Bax protein by inducing the ubiquitination. The E5-induced decrease in Bax expression was inhibited by a cyclooxygenase-2 (COX-2) inhibitor, prostaglandin E2 (PGE(2)) receptor antagonists and cyclic adenosine monophosphate-dependent protein kinase (PKA) inhibitor. Treatment with PGE(2) decreased the expression of Bax and inhibited hydrogen peroxide-induced apoptosis of C-33A cells. We concluded that HPV16 E5 protein inhibits hydrogen peroxide-induced apoptosis of cervical cancer cells by stimulating the ubiquitin-proteasome-mediated degradation of Bax protein, and the pathway involves COX-2, PGE(2) and PKA. This finding suggests the possibility that HPV 16 E5 protein contributes to cervical carcinogenesis by inhibiting apoptosis of transformed cervical epithelial cells.
Oh
Jung-Min
JM
Interdisciplinary Graduate Program in Tumor Biology, Cancer Research Institute, Seoul National University College of Medicine, 28 Yongon-dong, Jongno-gu, Seoul 110-799, Korea.
Kim
Su-Hyeong
SH
Cho
Eun-Ah
EA
Song
Yong-Sang
YS
Kim
Woo-Ho
WH
Juhnn
Yong-Sung
YS
D000730:Androstadienes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001713:Biphenyl Compounds / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology*; D002461:Cell Line, Transformed / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D003513:Cycloheximide / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000502:physiology; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D005260:Female; D006801:Humans; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D009856:Oncogene Proteins, Viral / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D018078:Receptors, Prostaglandin E / Q000187:drug effects / Q000502:physiology; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013449:Sulfonamides / Q000494:pharmacology; D025801:Ubiquitin / Q000502:physiology*; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000473:pathology*; D000077191:Wortmannin; D044004:Xanthones / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000378:metabolism*; D000086082:Viroporin Proteins
D000730:Androstadienes; D001713:Biphenyl Compounds; D017868:Cyclic AMP-Dependent Protein Kinases; D003513:Cycloheximide; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D015232:Dinoprostone; D006861:Hydrogen Peroxide; D007546:Isoquinolines; D009363:Neoplasm Proteins; D009856:Oncogene Proteins, Viral; D046988:Proteasome Endopeptidase Complex; D034741:RNA, Small Interfering; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013449:Sulfonamides; D025801:Ubiquitin; D000077191:Wortmannin; D044004:Xanthones; D051028:bcl-2-Associated X Protein; C494826:BAX protein, human; C545644:PTGER2 protein, human; C545650:PTGER4 protein, human; C054859:oncogene protein E5, Human papillomavirus type 16; D000086082:Viroporin Proteins; C053876:6-isopropoxy-9-oxoxanthene-2-carboxylic acid; C046926:AH 23848; C496540:PTGS2 protein, human; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide