Zhang Yudi, Bai Changmin, Lu Dan, Wu Xia, Gao Lili, Zhang Weiyuan
Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 10026, China.
Gynecological Department, Maternal and Child Health Hospital of Shanxi Province, Xi'an, 710003, Shanxi, China.
Biotechnol Lett. 2016 Feb;38(2):357-65. doi: 10.1007/s10529-015-1968-0. Epub 2015 Sep 30.
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.
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.
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.
确定内质网（ER）应激和自噬在硼替佐米诱导人宫颈癌来源的HeLa细胞和CaSki细胞凋亡中的作用。
硼替佐米处理激活了凋亡，HeLa细胞和CaSki细胞中裂解的半胱天冬酶-3和裂解的聚（ADP-核糖）聚合酶表达增加证明了这一点。硼替佐米还诱导线粒体膜电位丧失，增加ER应激相关蛋白GRP78、ATF4和CCAAT增强子结合蛋白同源蛋白的水平，并影响自噬相关蛋白的表达；增加LC3-II和ATG5-ATG12的水平，降低p62的水平。当我们将硼替佐米与ER应激激活剂衣霉素或自噬抑制剂3-甲基腺嘌呤或氯喹联合使用时，细胞生长抑制和凋亡明显增强。
硼替佐米激活凋亡信号，ER应激的激活和自噬的抑制增强了硼替佐米的细胞毒性，表明这些联合治疗可能是治疗宫颈癌的潜在化疗策略。
