Yudi Zhang1, Changmin Bai2, Dan Lu3, Xia Wu4, Lili Gao5, Weiyuan Zhang6. 1. Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 10026, China. 431097284@qq.com. 2. Gynecological Department, Maternal and Child Health Hospital of Shanxi Province, Xi'an, 710003, Shanxi, China. 1007866405@qq.com. 3. Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 10026, China. yinghua1168@163.com. 4. Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 10026, China. zhaodongxucc@126.com. 5. Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 10026, China. binzhangccc@126.com. 6. Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 10026, China. zhangweiyuan1168@163.com.
Abstract
OBJECTIVES: To determine the role of endoplasmic reticulum (ER) stress and autophagy in apoptosis induced by bortezomib in human cervical cancer-derived HeLa cells and CaSki cells. RESULTS: Bortezomib treatment activated apoptosis, evidenced by increased expression of cleaved caspase-3 and cleaved PARP in both HeLa cells and CaSki cells. Bortezomib also induced the loss of the mitochondrial membrane potential, increased the level of ER stress-associated proteins GRP78, ATF4, and CCAAT-enhancer-binding protein homologous protein, and affected the expression of autophagy-related proteins; increasing the levels of LC3-II and ATG5-ATG12 and decreasing the level of p62. When we combined bortezomib with the ER stress activator tunicamycin, or autophagy inhibitors 3-methyladenine or chloroquine, cell growth inhibition and apoptosis were markedly enhanced. CONCLUSIONS: Bortezomib activates apoptosis signaling, and activation of ER stress and inhibition of autophagy enhances the cytotoxicity of bortezomib, suggesting that these combination treatments may be potential chemotherapy strategies for treating cervical cancer.
OBJECTIVES: To determine the role of endoplasmic reticulum (ER) stress and autophagy in apoptosis induced by bortezomib in humancervical cancer-derived HeLa cells and CaSki cells. RESULTS:Bortezomib treatment activated apoptosis, evidenced by increased expression of cleaved caspase-3 and cleaved PARP in both HeLa cells and CaSki cells. Bortezomib also induced the loss of the mitochondrial membrane potential, increased the level of ER stress-associated proteins GRP78, ATF4, and CCAAT-enhancer-binding protein homologous protein, and affected the expression of autophagy-related proteins; increasing the levels of LC3-II and ATG5-ATG12 and decreasing the level of p62. When we combined bortezomib with the ER stress activator tunicamycin, or autophagy inhibitors 3-methyladenine or chloroquine, cell growth inhibition and apoptosis were markedly enhanced. CONCLUSIONS:Bortezomib activates apoptosis signaling, and activation of ER stress and inhibition of autophagy enhances the cytotoxicity of bortezomib, suggesting that these combination treatments may be potential chemotherapy strategies for treating cervical cancer.