Nuclear Survivin Abrogates Multiple Cell Cycle Checkpoints and Enhances Viral Oncolysis

生存素 细胞周期 生物 有丝分裂 癌症研究 溶瘤病毒 赫拉 第1周 凋亡抑制因子 细胞周期蛋白依赖激酶1 细胞生物学 细胞周期检查点 细胞凋亡 夏普 细胞周期蛋白B1 程序性细胞死亡 细胞 半胱氨酸蛋白酶 生物化学 肿瘤细胞
作者
Claire M. Connell,Sally P. Wheatley,Iain A. McNeish
出处
期刊:Cancer Research [American Association for Cancer Research]
卷期号:68 (19): 7923-7931 被引量:41
标识
DOI:10.1158/0008-5472.can-08-0817
摘要

Abstract Survivin (BIRC5) promotes cell division and survival with roles as chromosomal passenger protein and inhibitor of apoptosis protein (IAP). It is overexpressed in many cancers and is associated with resistance to chemotherapy and radiation. Previously, we showed that expression of survivin within the nucleus of HeLa cells accelerates its degradation and blocks apoptosis inhibition without affecting localization during mitosis. Here, we have investigated the effects of survivin on cell cycle control and potential therapeutic consequences using HeLa and IGROV1 cells expressing wild-type and nuclear-targeted survivin. We show that overexpression of survivin, especially within the nucleus, increases control over G1-S checkpoint via increased nuclear accumulation of cyclin D and cyclin-dependent kinase 4 and subsequent pRb phosphorylation. We investigated the influence of survivin on the activity of the E1A CR2-deleted oncolytic adenovirus dl922-947, which depends critically on an aberrant G1-S checkpoint. Nuclear expression of survivin augments virus-induced S-phase induction and increases viral protein expression and overall viral replication. There is a consequent increase in antitumor activity both in vitro and in vivo. The increased dl922-947 activity is restricted to malignant cells and is not associated with induction of apoptosis, nor does it rely on the role of survivin as an IAP. In addition, we observe the appearance of a large ≥4N population coincident with multiple mitotic defects in dl922-947–infected cells, both of which are significantly increased by nuclear survivin. This indicates that adenoviral activity is facilitated by abrogation of multiple cell cycle checkpoints and can be enhanced by expression of survivin within the nucleus. [Cancer Res 2008;68(19):7923–31]
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