Resveratrol-induced p53-independent apoptosis of human nasopharyngeal carcinoma cells is correlated with the downregulation of ΔNp63.
ΔNp63, the N-terminal truncated isoform of p63, has been found to be overexpressed in several human epithelial cancers, including nasopharyngeal carcinomas (NPCs), suggesting a function in carcinogenesis. Trans-resveratrol (RSV) has been shown to exert proapoptotic activities through a p53-dependent or p53-independent pathway in various cancer cells. However, the effects of RSV on NPC are still unexplored. In this study, we investigated the apoptotic effects of RSV on ΔNp63-overexpressing NPC cell lines. We showed that RSV (12-100 μ) induced dose-dependent growth suppression, cell-cycle arrest in the S phase and caspase-dependent apoptosis in NPC-TW076 and NPC-TW039 cells. The RSV effect was accompanied by the downregulation of ΔNp63 and the upregulation of p53 protein in a dose-dependent manner. By using small-interfering RNA (siRNA) technology, we found that the targeted silencing of ΔNp63 induced apoptosis and sensitized the NPC cells to RSV-induced apoptosis through caspase-3 activation, whereas suppression of p53 by siRNA did not inhibit RSV-induced apoptosis. Furthermore, transfection with p53 siRNA or pretreatment with caspase inhibitors (Z-VAD-fmk or Z-DEVD-fmk) had no influence on the RSV downregulation of ΔNp63. Interestingly, ecoptic expression of ΔNp63 did not significantly block RSV-induced cell death and was also downregulated after RSV treatment. Downregulation of ΔNp63 by RSV was shown to occur at the mRNA transcript and post-translational levels. Importantly, RSV enhanced chemotheraptic drug-induced apoptosis in NPC and two human carcinoma cell lines, HT1376 and Hep3B cells. These results suggested that ΔNp63, but not p53, is a molecular target of RSV-induced apoptosis and the regulation of ΔNp63 expression by RSV may provide a therapeutic effect of RSV in human NPC.
Chow
S-E
SE
Center for General Studies, Chang Gung University, Taoyuan, Taiwan, ROC. chowse@mail.cgu.edu.tw
Wang
J-S
JS
Chuang
S-F
SF
Chang
Y-L
YL
Chu
W-K
WK
Chen
W-S
WS
Chen
Y-W
YW
D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation; D006801:Humans; D009303:Nasopharyngeal Neoplasms / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D016588:Anticarcinogenic Agents; D034741:RNA, Small Interfering; D013267:Stilbenes; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D000077185:Resveratrol