Survivin, versatile modulation of cell division and apoptosis in cancer

The results proved that survivin is a reliable marker of aggressive and unfavorable disease, signaling abbreviated overall survival, increased rates of recurrences, resistance to therapy and reduced apoptotic index, in vivo

Dario C Altieri

2003

Scholarcy highlights

  • At 16.5 kDa, survivin is the smallest mammalian member of the inhibitor of apoptosis gene family
  • For endothelial cells stimulated with nonmitogenic IL-11, or pleural effusion lymphoma cells sustained by autocrine VEGF, IL-6 or IL-10, increased survivin expression was shown to be dependent on STAT3 activation
  • Survivin localizes to various components of the mitotic apparatus, including centrosomes, microtubules of the metaphase and anaphase spindle, and the remnants of the mitotic apparatus – midbodies
  • A broader role of survivin in cell division became apparent in antibody microinjection studies, which revealed a composite phenotype of prolonged metaphase arrest, occasionally followed by apoptosis, formation of multipolar mitotic spindles, and defects in chromosome attachments
  • The question as to whether survivin had a role in apoptosis inhibition, similar to other mammalian IAPs, or whether its function was limited to cell division, as with IAPs in yeast and C. elegans, has frequently been asked
  • Mutation of Thr34 in survivin abolishes a phosphorylation site for the mitotic kinase p34cdc2, and results in a dominantnegative phenotype with induction of apoptosis and anticancer activity, in vivo. To reproduce this effect with a more flexible pharmacologic approach, antagonists of cyclin-dependent kinases, flavopiridol, or the more p34cdc2-specific inhibitor, Purv.A, were tested in tumor cells arrested at mitosis with taxol, which induces hyperphosphorylation of survivin on Thr34
  • Progress has been made at improving the antitumor efficacy of antisense oligonucleotides, and various active sequences have been independently reported to suppress survivin expression and induce tumor cell apoptosis in vitro and in vivo

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