Nuclear survivin abrogates multiple cell cycle checkpoints and enhances viral oncolysis.
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 G(1)-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 G(1)-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 >or=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.
Connell
Claire M
CM
Centre for Molecular Oncology and Imaging, Institute of Cancer, Barts and the London School of Medicine and Dentistry, London, United Kingdom.
Wheatley
Sally P
SP
McNeish
Iain A
IA
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002453:Cell Cycle / Q000235:genetics* / Q000502:physiology; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D003131:Combined Modality Therapy; D005260:Female; D018816:Genes, cdc / Q000502:physiology; D015316:Genetic Therapy; D006367:HeLa Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009369:Neoplasms / Q000628:therapy*; D019913:Nuclear Localization Signals / Q000235:genetics / Q000378:metabolism; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000502:physiology*; D000077022:Survivin; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D019913:Nuclear Localization Signals; D000077022:Survivin