Induction of melanoma cell apoptosis and inhibition of tumor growth using a cell-permeable survivin antagonist

H. Yan, J. Thomas, T. Liu, D. Raj, N. London, T. Tandeski, Sancy Leachman, R. M. Lee, D. Grossman

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

The inhibitor of apoptosis gene family member Survivin is highly expressed in most tumors, and appears to be a promising target for cancer therapy. Although a variety of Survivin antagonists have been shown to induce apoptosis in malignant cells, the potential utility of these agents is limited by inefficient delivery and cell impermeability. We generated recombinant fusion proteins containing the TAT protein transduction domain and either wild-type Survivin (TAT-Surv-WT) or a dominant-negative mutant (TAT-Surv-T34A). The TAT-Surv proteins were purified by sequential affinity and ion-exchange chromatography, and at 30nM concentration demonstrated rapid entry into cells at 30min. Whereas TAT-Surv-WT had minimal effect on YUSAC2 or WM793 melanoma cells, TAT-Surv-T34A induced cell detachment, DNA fragmentation, caspase-3 activation and mitochondrial release of apoptosis-inducing factor at low μM concentrations. Intraperitoneal (i.p.) injection of mice bearing subcutaneous YUSAC2 xenografts with TAT-Surv-T34A (10mg/kg) was associated with rapid tumor accumulation at 1h, and increased tumor cell apoptosis and aberrant nuclei formation in situ. Repeated i.p. injection of TAT-Surv-T34A resulted in a 40-50% reduction in growth and mass of established tumors, compared to those similarly injected with saline buffer or TAT-Surv-WT. These studies demonstrate the feasibility of systemic tumor treatment using a cell-permeable Survivin antagonist.

Original languageEnglish (US)
Pages (from-to)6968-6974
Number of pages7
JournalOncogene
Volume25
Issue number52
DOIs
Publication statusPublished - Nov 2 2006
Externally publishedYes

    Fingerprint

Keywords

  • Apoptosis
  • Melanoma
  • Survivin
  • TAT
  • Xenograft

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Yan, H., Thomas, J., Liu, T., Raj, D., London, N., Tandeski, T., ... Grossman, D. (2006). Induction of melanoma cell apoptosis and inhibition of tumor growth using a cell-permeable survivin antagonist. Oncogene, 25(52), 6968-6974. https://doi.org/10.1038/sj.onc.1209676