Dominant-negative ATF5 rapidly depletes survivin in tumor cells
Xiaotian Sun1, James M Angelastro2, David Merino1,3
1Department of Pathology and Cell Biology, Columbia University, New York, NY, 10032, USA.
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.
Insights
Dominant-negative ATF5 (dn-ATF5) selectively kills cancer cells by depleting survivin, a protein crucial for tumor survival. This novel mechanism offers a potential therapeutic advantage over targeting survivin alone.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Survivin (BIRC5) is highly expressed in numerous cancers and is a recognized therapeutic target.
- Effective anti-survivin drugs are still under development, highlighting the need for novel strategies.
Purpose of the Study:
- To investigate the effect of dominant-negative ATF5 (dn-ATF5) on survivin expression in cancer cells.
- To elucidate the mechanisms by which dn-ATF5 induces cancer cell death.
Main Methods:
- Delivery of vector-delivered and cell-penetrating dn-ATF5 into various tumor cell lines.
- Analysis of survivin mRNA and protein levels.
- Investigation of proteasomal turnover and deubiquitinase USP9X involvement.
- Assessment of survivin overexpression on dn-ATF5-induced apoptosis.
Main Results:
- dn-ATF5 significantly depletes both survivin mRNA and protein levels in diverse cancer cell lines.
- Survivin depletion is mediated by enhanced proteasomal turnover and reduced USP9X levels.
- Survivin loss precedes dn-ATF5-induced cancer cell death.
- Overexpression of survivin does not rescue cells from dn-ATF5-induced apoptosis, indicating multiple death pathways.
Conclusions:
- dn-ATF5 effectively reduces survivin levels, contributing to cancer cell death.
- dn-ATF5 induces cancer cell apoptosis through mechanisms beyond survivin depletion.
- Cell-penetrating dn-ATF5 variants show promise as a therapeutic strategy with potential advantages over survivin-targeted treatments.
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