Depletion of securin increases arsenite-induced chromosome instability and apoptosis via a p53-independent pathway.
Arsenic is a pathologic factor of cardiovascular diseases and cancers; nevertheless, it also acts as an anticancer agent effective on acute promyelocytic leukemia and multiple myeloma. Securin, a proposed proto-oncogene, regulates cell proliferation and tumorigenesis. However, roles of securin on the arsenic-induced cell cycle arrest and apoptosis remain unknown. In this study, the effects of sodium arsenite on the expression of securin in two tissue types of cell lines, the vascular endothelial and colorectal epithelial cells, were investigated. Arsenite (8-16 microM, 24 h) increased the cytotoxicity, apoptosis, and growth inhibition in both endothelial and epithelial cells. The levels of phospho-CDC2 (threonine-161), CDC2, and cyclin B1 proteins were decreased, and the G2/M fractions were increased by arsenite. Concomitantly, arsenite markedly diminished the securin protein expression and induced the abnormal sister chromatid separation. The depletion of securin proteins increased the induction of mitotic arrest, aberrant chromosome segregation, and apoptosis after arsenite treatment. p53, a tumor suppressor protein, balances the cell survival and apoptosis. Arsenite raised the levels of phospho-p53 (serine-15) and p53 (DO-1) proteins in both the securin-wild-type and -null cells. The p53-functional cells were more susceptible than the p53-mutational cells to arsenite on the cytotoxicity and apoptosis. Besides, arsenite decreased the levels of securin proteins to a similar degree in both the p53-functional and -mutational cells. Together, it is the first time to demonstrate that the inhibition of securin expression induced by arsenite increases the chromosomal instability and apoptosis via a p53-independent pathway.
Chao
Jui-I
JI
Molecular Anticancer Laboratory, Institute of Pharmacology and Toxicology, College of Life Sciences, Tzu Chi University, Hualien, Taiwan. chaoji@mail.tcu.edu.tw
Hsu
Shih-Hsin
SH
Tsou
Tsui-Chun
TC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D018053:Arsenites / Q000633:toxicity*; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D019926:Cyclin B / Q000378:metabolism; D056744:Cyclin B1; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004791:Enzyme Inhibitors / Q000633:toxicity*; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D064249:Securin; D012854:Sister Chromatid Exchange / Q000187:drug effects*; D017670:Sodium Compounds / Q000633:toxicity*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D018053:Arsenites; D002352:Carrier Proteins; C534700:Ccnb1 protein, mouse; D019926:Cyclin B; D056744:Cyclin B1; D004791:Enzyme Inhibitors; D064249:Securin; D017670:Sodium Compounds; D016159:Tumor Suppressor Protein p53; C017947:sodium arsenite; D016203:CDC2 Protein Kinase