Survivin inhibition induces human neural tumor cell death through caspase-independent and -dependent pathways

Sai Latha Shankar, Sridhar Mani, Kathleen Norman O'Guin, Ekambar R. Kandimalla, Sudhir Agrawal, Bridget Shafit-Zagardo

Research output: Contribution to journalArticle

119 Scopus citations

Abstract

Survivin inhibits apoptosis during development and carcinogenesis and is absent in differentiated cells. To determine whether survivin inhibition induces cell death in neural tumor cells, survivin antisense oligonucleotides (SAO) were administered to a human neuroblastoma (MSN) and an oligodendroglioma (TC620) resulting in a dose-dependent reduction in survivin protein. Although 74% of the SAO-treated MSN cells were trypan blue+, PARP cleavage or activated caspase-3 was not observed. However nuclear translocation of AIF occurred and XIAP increased dramatically. Co-administration of z-Val-Ala-Asp(OMe)-fluoromethyl ketone (zVAD-fmk) with SAO did not inhibit cell death suggesting a caspase-independent mechanism of cell death. Propidium iodide (PI) staining revealed multiple large macronuclei with no apoptotic bodies supporting a role for survivin in cell division. By contrast, while 70% of the SAO-treated TC620 cells were trypan blue+, PARP was cleaved, cells were TUNEL+ and PI-staining revealed macronuclei and numerous apoptotic bodies. Co-treatment of the TC620 cells with SAO and zVAD-fmk blocked cell death. While no macronuclei or apoptotic bodies were observed there was a two-fold increase in metaphase cells. Our results suggest that survivin inhibition decreases the viability of human neural tumor cells and as a result of mitotic catastrophe, cell death can be initiated by either a classic apoptotic mechanism or a caspase-independent mechanism.

Original languageEnglish (US)
Pages (from-to)426-436
Number of pages11
JournalJournal of Neurochemistry
Volume79
Issue number2
DOIs
StatePublished - Nov 1 2001

Keywords

  • Antisense oligonucleotides
  • Apoptosis
  • Cell death
  • Human brain tumors
  • Survivin

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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