Jacob Naduparambil K, Cooley James V, Shirai Katsuyuki, Chakravarti Arnab
Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center, 410 W 12th Ave, Columbus, OH 43210, USA.
Onco Targets Ther. 2012;5:7-20. doi: 10.2147/OTT.S28147. Epub 2012 Feb 15.
Survivin is a critical regulator of mitosis, and an inhibitor of apoptosis which is overexpressed in almost all cancers. In the current study, cell cycle profiles of normal proliferating human umbilical vein endothelial cells, prostate cancer, and lung cancer cell lines expressing varying levels of survivin and its splice variants were compared using a novel functional complementation assay. Defects in chromosome segregation and cytokinesis that were observed after depletion of endogenous survivin were not complemented by any of the survivin splice variants: survivin-2B, survivin-3B, survivin-ΔEx3, or survivin-2A when expressed exogenously at a level comparable to endogenous full-length survivin. Survivin variants were not detectable at the endogenous protein level. Cancer cells with higher levels of full-length survivin and survivin-2B expression, exhibited reduced caspase-3 activation following doxorubicin treatment and radiation. Whereas earlier studies focused on function and expression levels of survivin specific to cancer cells, the current study brings forward the essential role of survivin in normal dividing cells. Full-length survivin was found to be associated with Aurora-B kinase in the chromosomal passenger complex and depletion of survivin mimics mitotic phenotypes observed after Aurora-B kinase inhibition, in cancer as well as normal proliferating cells. Thus, our study establishes survivin as a marker of proliferation, rather than a cancer specific marker. Therefore, systemic therapeutic interventions targeting survivin will affect cancer as well as normal proliferating cells.
生存素是有丝分裂的关键调节因子，也是一种凋亡抑制因子，在几乎所有癌症中均过度表达。在本研究中，使用一种新型功能互补试验比较了正常增殖的人脐静脉内皮细胞、前列腺癌细胞和肺癌细胞系的细胞周期谱，这些细胞系表达不同水平的生存素及其剪接变体。在内源性生存素缺失后观察到的染色体分离和胞质分裂缺陷，在以与内源性全长生存素相当的水平外源性表达时，未被任何生存素剪接变体（生存素-2B、生存素-3B、生存素-ΔEx3或生存素-2A）所互补。在内源性蛋白质水平未检测到生存素变体。全长生存素和生存素-2B表达水平较高的癌细胞，在阿霉素治疗和放疗后，半胱天冬酶-3的激活减少。早期研究聚焦于癌细胞特有的生存素的功能和表达水平，而本研究提出了生存素在正常分裂细胞中的重要作用。发现全长生存素在染色体乘客复合体中与极光激酶B相关，在癌症以及正常增殖细胞中，生存素的缺失模拟了极光激酶B抑制后观察到的有丝分裂表型。因此，我们的研究将生存素确立为增殖标志物，而非癌症特异性标志物。因此，针对生存素的全身治疗干预将影响癌症以及正常增殖细胞。
