Dominant-negative ATF5 rapidly depletes survivin in tumor cells

Xiaotian Sun, James M. Angelastro, David Merino, Qing Zhou, Markus D. Siegelin, Lloyd A. Greene

Research output: Contribution to journalArticle

Abstract

Survivin (BIRC5, product of the BIRC5 gene) is highly expressed in many tumor types and has been widely identified as a potential target for cancer therapy. However, effective anti-survivin drugs remain to be developed. Here we report that both vector-delivered and cell-penetrating dominant-negative (dn) forms of the transcription factor ATF5 that promote selective death of cancer cells in vitro and in vivo cause survivin depletion in tumor cell lines of varying origins. dn-ATF5 decreases levels of both survivin mRNA and protein. The depletion of survivin protein appears to be driven at least in part by enhanced proteasomal turnover and depletion of the deubiquitinase USP9X. Survivin loss is rapid and precedes the onset of cell death triggered by dn-ATF5. Although survivin downregulation is sufficient to drive tumor cell death, survivin over-expression does not rescue cancer cells from dn-ATF5-promoted apoptosis. This indicates that dn-ATF5 kills malignant cells by multiple mechanisms that include, but are not limited to, survivin depletion. Cell-penetrating forms of dn-ATF5 are currently being developed for potential therapeutic use and the present findings suggest that they may pose an advantage over treatments that target only survivin.

Original languageEnglish (US)
Article number709
JournalCell Death and Disease
Volume10
Issue number10
DOIs
StatePublished - Oct 1 2019

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Cell Death
Neoplasms
Therapeutic Uses
Tumor Cell Line
Proteins
Transcription Factors
Down-Regulation
Apoptosis
Messenger RNA
Pharmaceutical Preparations
Genes
Therapeutics
Deubiquitinating Enzymes
In Vitro Techniques

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Cite this

Dominant-negative ATF5 rapidly depletes survivin in tumor cells. / Sun, Xiaotian; Angelastro, James M.; Merino, David; Zhou, Qing; Siegelin, Markus D.; Greene, Lloyd A.

In: Cell Death and Disease, Vol. 10, No. 10, 709, 01.10.2019.

Research output: Contribution to journalArticle

Sun, Xiaotian ; Angelastro, James M. ; Merino, David ; Zhou, Qing ; Siegelin, Markus D. ; Greene, Lloyd A. / Dominant-negative ATF5 rapidly depletes survivin in tumor cells. In: Cell Death and Disease. 2019 ; Vol. 10, No. 10.
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