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.
Highlights
In North America and Europe, gynaecological cancer accounts for more than 1/10th of cancer deaths and new cases among women [1,2,3]
We recently reported the caspase3-dependent cleavage of Prostate apoptosis response-4 (Par-4) resulting in the accumulation of a 25kDa cleaved-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
Literature and data from cbioportal.org indicates that less than 2.5% of all cancer cases have a mutation or suppression of the Par-4 gene, excluding melanoma. This rate is even lower (
Summary
In North America and Europe, gynaecological cancer accounts for more than 1/10th of cancer deaths and new cases among women [1,2,3]. Ovarian cancer is the fifth leading cause of cancer death among women and is the gynaecological cancer causing the highest mortality rate [1,2,3,4,5]. Endometrial cancer is the most common gynaecological cancer with the highest rate of new cases each year [1,2,3, 6]. The role and regulation of Par-4 in ovarian and endometrial malignancies warrants further investigation
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