title: Post-translational regulation of the cleaved fragment of Par-4 in ovarian and endometrial cancer cells.
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.
authors.affiliation: Research Group in Cellular Signaling, Department of Medical Biology, Université du Québec à Trois-Rivières, Trois-Rivières, Québec G9A 5H7, Canada.
authors.forename: Kevin
authors.initials: K
authors.lastname: Brasseur
authors.affiliation: Research Group in Cellular Signaling, Department of Medical Biology, Université du Québec à Trois-Rivières, Trois-Rivières, Québec G9A 5H7, Canada.
authors.forename: François
authors.initials: F
authors.lastname: Fabi
authors.affiliation: Research Group in Cellular Signaling, Department of Medical Biology, Université du Québec à Trois-Rivières, Trois-Rivières, Québec G9A 5H7, Canada.
authors.forename: Pascal
authors.initials: P
authors.lastname: Adam
authors.affiliation: Research Group in Cellular Signaling, Department of Medical Biology, Université du Québec à Trois-Rivières, Trois-Rivières, Québec G9A 5H7, Canada.
authors.forename: Sophie
authors.initials: S
authors.lastname: Parent
authors.affiliation: Research Group in Cellular Signaling, Department of Medical Biology, Université du Québec à Trois-Rivières, Trois-Rivières, Québec G9A 5H7, Canada.
authors.forename: Laurent
authors.initials: L
authors.lastname: Lessard
authors.affiliation: Research Group in Cellular Signaling, Department of Medical Biology, Université du Québec à Trois-Rivières, Trois-Rivières, Québec G9A 5H7, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Asselin
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D016889:Endometrial Neoplasms / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D010051:Ovarian Neoplasms / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D055550:Protein Stability
chemical_list: D051017:Apoptosis Regulatory Proteins; D010446:Peptide Fragments; C101296:prostate apoptosis response-4 protein
keywords: MAPK; PI3K; Par-4; gynaecological cancers; proteasome