title: p38-NF-κB-promoted mitochondria-associated apoptosis and G2/M cell cycle arrest in norcantharidin-treated HeLa cells.
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 (ΔΨ(m)), 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.
authors.affiliation: China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Xiu
authors.initials: X
authors.lastname: Dong
authors.forename: Jian-Chun
authors.initials: JC
authors.lastname: Li
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Jiang
authors.forename: Ming-Yu
authors.initials: MY
authors.lastname: Xia
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Tashiro
authors.forename: Satoshi
authors.initials: S
authors.lastname: Onodera
authors.forename: Takashi
authors.initials: T
authors.lastname: Ikejima
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D015394:Molecular Structure; D016328:NF-kappa B / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology*; D013859:Thiocarbamates / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D011759:Pyrrolidines; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; C069741:norcantharidin; D048051:p38 Mitogen-Activated Protein Kinases