A Naturally Generated Decoy of the Prostate Apoptosis Response-4 Protein Overcomes Therapy Resistance in Tumors. Academic Article uri icon

Overview

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. Cancer Res; 77(15); 4039-50. ©2017 AACR.

publication date

  • June 16, 2017

Research

keywords

  • Apoptosis
  • Apoptosis Regulatory Proteins
  • Drug Resistance, Neoplasm
  • Neoplasms, Experimental

Identity

PubMed Central ID

  • PMC5540761

Scopus Document Identifier

  • 85026725590

Digital Object Identifier (DOI)

  • 10.1158/0008-5472.CAN-16-1970

PubMed ID

  • 28625975

Additional Document Info

volume

  • 77

issue

  • 15