Abstract
Previous study proved that norcantharidin (NCTD) could exert its anticancer activity in a variety of malignant cell lines, including human cervical carcinoma HeLa cells. In this study, we found that NCTD-activated p38 mitogen-activated protein kinase (p38 MAPK)-nuclear transcription factor kappa B (NF-κB) signaling pathway induced mitochondrial apoptotic pathway activation and G2/M cell cycle arrest in HeLa cells. NCTD-induced mitochondria-associated apoptosis was concomitant with the collapse of mitochondrial membrane potential (ΔΨm), translocation of Bax, down-regulation of Bcl-2 expression, and release of cytochrome c. NCTD-led G2/M cell-cycle arrest was associated with the up-regulated p21 and p-cdc25c expression and the down-regulated cyclin B and cdc2 expression. Treatment of the cells with p38 inhibitor SB203580 and NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) showed that p38 functioned upstream of NF-κB, while augmented apoptosis and cell cycle arrest were induced in response to NCTD with NF-κB activation. Intriguingly, NF-κB had a negative feedback regulatory effect on p38 activation. Moreover, NCTD-induced apoptosis and cell cycle arrest were significantly blocked by SB203580 and PDTC but not by pifithrin-α (p53 inhibitor). Therefore, p38–NF-κB induced mitochondrial apoptotic pathway and G2/M cell cycle arrest in NCTD-treated HeLa cells.
Acknowledgments
This study was financially supported by Department of Education of Liaoning Province (No. 2008441) and the National Key Scientific Project for New Drug Discovery and Development (2009ZX09301-012), 2009–2010, China.