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

Nikhil Hebbar1,2, Ravshan Burikhanov1, Nidhi Shukla2

  • 1Department of Radiation Medicine, University of Kentucky, Lexington, Kentucky.

Cancer Research
|June 20, 2017
PubMed

Insights

A prostate apoptosis response-4 (Par-4) fragment (PAF) acts as a molecular decoy. This fragment overcomes cancer therapy resistance by inhibiting a ubiquitin ligase, promoting apoptosis in resistant cells.

Area of Science:

  • Cancer Biology
  • Molecular Oncology
  • Tumor Microenvironment

Background:

  • Primary tumors exhibit heterogeneity, containing both therapy-sensitive and therapy-resistant cancer cells.
  • Therapy of sensitive cells within heterogeneous tumors can paradoxically induce apoptosis in resistant populations.

Purpose of the Study:

  • To identify mechanisms by which therapy-sensitive cells induce apoptosis in resistant cells within a heterogeneous tumor.
  • To investigate the role of prostate apoptosis response-4 (Par-4) in mediating this cross-talk and overcoming therapy resistance.

Main Methods:

  • Identification and characterization of a prostate apoptosis response-4 (Par-4) amino-terminal fragment (PAF).
  • Analysis of PAF's interaction with the ubiquitin ligase Fbxo45 and its effect on Par-4 proapoptotic function.
  • Assessment of PAF's ability to induce apoptosis and inhibit tumor growth in resistant cancer cells.

Main Results:

  • Therapy-sensitive cells release PAF upon caspase cleavage of Par-4.
  • PAF induces apoptosis in therapy-resistant cancer cells and inhibits tumor growth.
  • The VASA segment of Par-4 is crucial for Fbxo45 binding and degradation; PAF competitively inhibits this interaction, rescuing Par-4's proapoptotic function.

Conclusions:

  • A naturally generated fragment of Par-4 (PAF) acts as a molecular decoy to overcome cancer therapy resistance.
  • PAF inhibits the ubiquitin ligase Fbxo45, thereby restoring Par-4-mediated apoptosis in resistant cancer cells.
  • This mechanism highlights a novel strategy for targeting therapy resistance in heterogeneous tumors.

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