A Naturally Generated Decoy of the Prostate Apoptosis Response-4 Protein Overcomes Therapy Resistance in Tumors

Authors

Nikhil Hebbar, University of KentuckyFollow
Ravshan Burikhanov, University of KentuckyFollow
Nidhi Shukla, University of KentuckyFollow
Shirley Qiu, University of KentuckyFollow
Yanming Zhao, University of KentuckyFollow
Kojo S. J. Elenitoba-Johnson, University of Pennsylvania
Vivek M. Rangnekar, University of KentuckyFollow

Abstract

Primary tumors are often heterogeneous, composed of therapy-sensitive and emerging therapy-resistant cancer cells. Interestingly, treatment of therapy-sensitive tumors in heterogeneous tumor microenvironments results in apoptosis of therapy-resistant tumors. In this study, we identify a prostate apoptosis response-4 (Par-4) amino-terminal fragment (PAF) that is released by diverse therapy-sensitive cancer cells following therapy-induced caspase cleavage of the tumor suppressor Par-4 protein. PAF caused apoptosis in cancer cells resistant to therapy and inhibited tumor growth. A VASA segment of Par-4 mediated its binding and degradation by the ubiquitin ligase Fbxo45, resulting in loss of Par-4 proapoptotic function. Conversely, PAF, which contains this VASA segment, competitively bound to Fbxo45 and rescued Par-4–mediated induction of cancer cell–specific apoptosis. Collectively, our findings identify a molecular decoy naturally generated during apoptosis that inhibits a ubiquitin ligase to overcome therapy resistance in tumors.

Document Type

Article

Publication Date

8-2017

Notes/Citation Information

Published in Cancer Research, v. 77, issue 15, p. 4039-4050.

© 2017 American Association for Cancer Research

The copyright holder has granted the permission for posting the article here.

The document available for download is the authors' post-peer-review final draft of the article.

Digital Object Identifier (DOI)

https://doi.org/10.1158/0008-5472.CAN-16-1970

Funding Information

V.M. Rangnekar was recipient of NIH grants R01CA187273, R01CA165469, and R21CA179283.

Related Content

Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

Repository Citation

Hebbar, Nikhil; Burikhanov, Ravshan; Shukla, Nidhi; Qiu, Shirley; Zhao, Yanming; Elenitoba-Johnson, Kojo S. J.; and Rangnekar, Vivek M., "A Naturally Generated Decoy of the Prostate Apoptosis Response-4 Protein Overcomes Therapy Resistance in Tumors" (2017). Radiation Medicine Faculty Publications. 18.
https://uknowledge.uky.edu/radmed_facpub/18