Post-translational regulation of the cleaved fragment of Par-4 in ovarian and endometrial cancer cells

Oncotarget. 2016 Jun 14;7(24):36971-36987. doi: 10.18632/oncotarget.9235.

Abstract

We recently reported the caspase3-dependent cleavage of Par-4 resulting in the accumulation of a 25kDa cleaved-Par-4 (cl-Par-4) fragment and we investigated in the present study the mechanisms regulating this fragment using cl-Par-4-expressing stable clones derived from ovarian and endometrial cancer cell lines.Cl-Par-4 protein was weakly express in all stable clones despite constitutive expression. However, upon cisplatin treatment, cl-Par-4 levels increased up to 50-fold relative to baseline conditions. Treatment of stable clones with proteasome and translation inhibitors revealed that cisplatin exposure might in fact protect cl-Par-4 from proteasome-dependent degradation. PI3K and MAPK pathways were also implicated as evidenced by an increase of cl-Par-4 in the presence of PI3K inhibitors and a decrease using MAPK inhibitors. Finally using bioinformatics resources, we found diverse datasets showing similar results to those we observed with the proteasome and cl-Par-4 further supporting our data.These new findings add to the complex mechanisms regulating Par-4 expression and activity, and justify further studies addressing the biological significance of this phenomenon in gynaecological cancer cells.

Keywords: MAPK; PI3K; Par-4; gynaecological cancers; proteasome.

MeSH terms

  • Apoptosis Regulatory Proteins / metabolism*
  • Cell Line, Tumor
  • Endometrial Neoplasms / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic / physiology*
  • Humans
  • Ovarian Neoplasms / metabolism*
  • Peptide Fragments / metabolism
  • Protein Processing, Post-Translational
  • Protein Stability

Substances

  • Apoptosis Regulatory Proteins
  • Peptide Fragments
  • prostate apoptosis response-4 protein