Sulindac induces specific degradation of the HPV oncoprotein E7 and causes growth arrest and apoptosis in cervical carcinoma cells.
Sulindac, a nonsteroidal anti-inflammatory drug (NSAID), induces growth arrest in HeLa cells and causes strong inhibition of the G1 to S transition of the cell cycle in a concentration-dependent manner. The G1 arrest is preceded by suppression of cyclin E and A, inactivation of cdk2, and the complete loss of the viral oncoprotein E7, despite ongoing HPV transcription. As shown by inhibitors specific for cyclooxygenase (COX) 1 and 2 loss of E7 is COX-independent. Moreover, inhibition of the proteasome activity with MG132 partially blocked the ability of sulindac to suppress E7 suggesting that sulindac induces degradation of E7 by the proteasomal pathway. In addition to inhibiting growth, sulindac strongly induces apoptosis, which can be abrogated by using the general caspase inhibitor zVAD-fmk. Unchanged expression of the pro-apoptotic protein Bax and suppression of the anti-apoptotic molecules Bcl-2 and Bcl-x(L) argues for the engagement of the mitochondrial apoptotic pathway. These results support the notion that sulindac is a potent growth inhibitor and inducer of apoptosis on cervical cancer cells in vitro and may offer new perspectives as a chemopreventive or supplementary anti-cervical cancer drug.
Karl
Theresia
T
Deutsches Krebsforschungszentrum, Forschungsschwerpunkt Angewandte Tumorvirologie, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
Seibert
Nadine
N
Stöhr
Michael
M
Osswald
Hans
H
Rösl
Frank
F
Finzer
Patrick
P
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015152:Blotting, Northern; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects*; D016213:Cyclins / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D016193:G1 Phase / Q000187:drug effects; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D000077239:Meloxicam; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D016196:S Phase / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D013467:Sulindac / Q000494:pharmacology*; D013843:Thiazines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000473:pathology / Q000821:virology; D000096926:Benzenesulfonamides
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016213:Cyclins; D051546:Cyclooxygenase 2; D016861:Cyclooxygenase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D004268:DNA-Binding Proteins; D007976:Leupeptins; D000077239:Meloxicam; D009856:Oncogene Proteins, Viral; D046988:Proteasome Endopeptidase Complex; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011720:Pyrazoles; D013449:Sulfonamides; D013467:Sulindac; D013843:Thiazines; D013844:Thiazoles; C119130:4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C052633:E7 protein, Human papillomavirus type 18; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde