title: Prostate apoptosis response-4 is expressed in normal cholangiocytes, is down-regulated in human cholangiocarcinoma, and promotes apoptosis of neoplastic cholangiocytes when induced pharmacologically.
abstract: 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 treatment strategy.
authors: Department of Human Anatomy, University of Rome Sapienza, Rome, Italy.
authors: Antonio
authors: A
authors: Franchitto
authors: Alessia
authors: A
authors: Torrice
authors: Rossella
authors: R
authors: Semeraro
authors: Cristina
authors: C
authors: Napoli
authors: Gennaro
authors: G
authors: Nuzzo
authors: Felice
authors: F
authors: Giuliante
authors: Gianfranco
authors: G
authors: Alpini
authors: Guido
authors: G
authors: Carpino
authors: Pasquale Bartolomeo
authors: PB
authors: Berloco
authors: Luciano
authors: L
authors: Izzo
authors: Antonio
authors: A
authors: Bolognese
authors: Paolo
authors: P
authors: Onori
authors: Anastasia
authors: A
authors: Renzi
authors: Alfredo
authors: A
authors: Cantafora
authors: Eugenio
authors: E
authors: Gaudio
authors: Domenico
authors: D
authors: Alvaro
mesh_terms: D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018281:Cholangiocarcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D015536:Down-Regulation; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007124:Immunoenzyme Techniques; D007211:Indoles / Q000494:pharmacology; D008099:Liver / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D054358:Withanolides / Q000494:pharmacology
chemical_list: C512018:1,1-bis(3'-indolyl)methane; D051017:Apoptosis Regulatory Proteins; D007211:Indoles; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D054358:Withanolides; C101296:prostate apoptosis response-4 protein; C009684:withaferin A