Prostate apoptosis response-4 (Par-4) is a tumor suppressor
protein that sensitizes cells to apoptosis; therefore, Par-4 modulation has therapeutic potential.
No data currently exist on Par-4 expression in cholangiocarcinoma (CCA). We evaluated the expression
of Par-4 in normal and neoplastic cholangiocytes and the effects of its pharmacological or genetic modulation.
The study was performed in human and rat
liver, CCA patient biopsies, and two CCA cell lines.
PAR-4 was expressed in normal rat and human cholangiocytes, but its expression levels decreased in
both human CCA and CCA cell lines. In both intrahepatic and extrahepatic CCA, Par-4 expression (as
shown by immunohistochemistry) was inversely correlated with markers of proliferation (eg, proliferating
cellular nuclear antigen) and directly correlated with apoptotic markers (eg, Bax and Bax/BCL2 ratio).
Par-4 expression was decreased during CCA cell proliferation
but was enhanced after apoptosis induction.
Pharmacological induction of Par-4 expression in CCA cell lines by diindolymethane or withaferin A
promoted activation of apoptosis and inhibition of proliferation. In contrast, specific Par-4 silencing by
small-interfering RNA determined activation of CCA cell line proliferation. Par-4 is expressed in rat and human cholangiocytes and is down-regulated in both human CCA
and CCA cell lines. Par-4 protein levels decrease during cell
proliferation but increase during apoptosis. Pharmacological
or genetic induction of Par-4 determines apoptosis of CCA cells, suggesting Par-4 targeting as a CCA
- Prostate apoptosis response-4