Zhang Wenfeng, Xu Jie, Ji Dexiang, Li Zhangyun, He Wenxing, Yang Fei, Lan Huiyin, Wang Yu, Wu Zhengping, Liu Xiaoshan, Huang Shanhua, Li Longkun, Zhou Weihua
Department of Infectious Disease, the First Affiliated Hospital, Nanchang University, Nanchang, China.
Department of Oncology, the Second Affiliated Hospital, Nanchang University, Nanchang, China.
Cell Physiol Biochem. 2017;43(1):94-107. doi: 10.1159/000480322. Epub 2017 Aug 25.
BACKGROUND/AIMS: CyclinG1 (CycG1) is frequently overexpressed in solid tumors and overexpression of CycG1 promotes cell survival upon paclitaxel exposure by inducing polyploidy. Whether and how CycG1 regulates polyploidization caused by small molecular targeted inhibitors remains unclear.
Immunohistochemistry and immunoblotting were utilized to examine protein expression. Cell proliferation was measured by ATPlite assay, and cell cycle distribution and apoptosis were measured by flow cytometry and/or DNA fragmentation assays.
Overexpression of CycG1 in breast cancer cells caused apoptosis-resistant polyploidy upon treatment with Aurora kinase inhibitor, ZM447439 (ZM). Addition of ABT-263, a small-molecule BH3 mimetic, to ZM, produced a synergistic loss of cell viability with greater sustained tumor growth inhibition in breast cancer cell lines. Decrease of Mcl-1 and increase of NOXA caused by ZM treatment, were responsible for the synergy. Furthermore, CycG1 was highly expressed in Triple-Negative-Breast-Cancer patients treated with paclitaxel and was paralleled by decreased cell survival.
CycG1 is a crucial factor in ZM-induced polyploidy resistance, and ABT-263/ZM combination hold therapeutic utility in the CycG1-amplified subset of breast cancer and CycG1, thus, is a promising target in breast cancer.
背景/目的：细胞周期蛋白G1（CycG1）在实体瘤中常过度表达，CycG1的过表达通过诱导多倍体促进紫杉醇暴露后的细胞存活。CycG1是否以及如何调节小分子靶向抑制剂引起的多倍体化仍不清楚。
采用免疫组织化学和免疫印迹法检测蛋白表达。通过ATPlite检测法测定细胞增殖，通过流式细胞术和/或DNA片段化检测法测定细胞周期分布和凋亡。
乳腺癌细胞中CycG1的过表达在用极光激酶抑制剂ZM447439（ZM）处理后导致抗凋亡多倍体。将小分子BH3模拟物ABT-263添加到ZM中，在乳腺癌细胞系中产生了协同的细胞活力丧失以及更强的持续肿瘤生长抑制作用。ZM处理导致的Mcl-1减少和NOXA增加是协同作用的原因。此外，在用紫杉醇治疗的三阴性乳腺癌患者中CycG1高度表达，同时细胞存活率降低。
CycG1是ZM诱导的多倍体抗性的关键因素，ABT-263/ZM组合在CycG1扩增的乳腺癌亚组中具有治疗效用，因此，CycG1是乳腺癌中一个有前景的靶点。
