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.
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V.M. Rangnekar was recipient of NIH grants R01CA187273, R01CA165469, and R21CA179283.
Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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.