title: Survivin splice variants are not essential for mitotic progression or inhibition of apoptosis induced by doxorubicin and radiation.
abstract: 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.
authors.affiliation: Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center, 410 W 12th Ave, Columbus, OH 43210, USA.
authors.forename: Naduparambil K
authors.initials: NK
authors.lastname: Jacob
authors.forename: James V
authors.initials: JV
authors.lastname: Cooley
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Shirai
authors.forename: Arnab
authors.initials: A
authors.lastname: Chakravarti