A Naturally Generated Decoy of the Prostate Apoptosis Response-4 Protein Overcomes Therapy Resistance in Tumors.
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.Cancer Res; 77(15); 4039-50. ©2017 AACR.
Mesh Terms:
Animals, Apoptosis, Apoptosis Regulatory Proteins, Blotting, Western, Cell Line, Tumor, Drug Resistance, Neoplasm, Humans, Immunoprecipitation, Male, Mice, Mice, Nude, Neoplasms, Experimental, Peptides, Xenograft Model Antitumor Assays
Animals, Apoptosis, Apoptosis Regulatory Proteins, Blotting, Western, Cell Line, Tumor, Drug Resistance, Neoplasm, Humans, Immunoprecipitation, Male, Mice, Mice, Nude, Neoplasms, Experimental, Peptides, Xenograft Model Antitumor Assays
Cancer Res.
Date: Aug. 01, 2017
PubMed ID: 28625975
View in: Pubmed Google Scholar
Download Curated Data For This Publication
208011
Switch View:
- Interactions 1