Prostate apoptosis response-4 is expressed in normal cholangiocytes, is down-regulated in human cholangiocarcinoma, and promotes apoptosis of neoplastic cholangiocytes when induced pharmacologically

Antonio Franchitto, Alessia Torrice, Rossella Semeraro, Cristina Napoli, Gennaro Nuzzo, Felice Giuliante, Gianfranco Alpini, Guido Carpino, Pasquale Bartolomeo Berloco, Luciano Izzo, Antonio Bolognese, Paolo Onori, Anastasia Renzi, Alfredo Cantafora, Eugenio Gaudio, Domenico Alvaro

Risultato della ricerca: Contributo in rivistaArticolopeer review

12 Citazioni (Scopus)

Abstract

Prostate apoptosis response-4 (Par-4) is a tumor suppressor\r\nprotein that sensitizes cells to apoptosis; therefore, Par-4 modulation has therapeutic potential.\r\nNo data currently exist on Par-4 expression in cholangiocarcinoma (CCA). We evaluated the expression\r\nof Par-4 in normal and neoplastic cholangiocytes and the effects of its pharmacological or genetic modulation.\r\nThe study was performed in human and rat\r\nliver, CCA patient biopsies, and two CCA cell lines.\r\nPAR-4 was expressed in normal rat and human cholangiocytes, but its expression levels decreased in\r\nboth human CCA and CCA cell lines. In both intrahepatic and extrahepatic CCA, Par-4 expression (as\r\nshown by immunohistochemistry) was inversely correlated with markers of proliferation (eg, proliferating\r\ncellular nuclear antigen) and directly correlated with apoptotic markers (eg, Bax and Bax/BCL2 ratio).\r\nPar-4 expression was decreased during CCA cell proliferation\r\nbut was enhanced after apoptosis induction.\r\nPharmacological induction of Par-4 expression in CCA cell lines by diindolymethane or withaferin A\r\npromoted activation of apoptosis and inhibition of proliferation. In contrast, specific Par-4 silencing by\r\nsmall-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\r\nand CCA cell lines. Par-4 protein levels decrease during cell\r\nproliferation but increase during apoptosis. Pharmacological\r\nor genetic induction of Par-4 determines apoptosis of CCA cells, suggesting Par-4 targeting as a CCA\r\ntreatment strategy.
Lingua originaleInglese
pagine (da-a)1779-1790
Numero di pagine12
RivistaTHE AMERICAN JOURNAL OF PATHOLOGY
Volume177
Numero di pubblicazione177
DOI
Stato di pubblicazionePubblicato - 2010

Keywords

  • Cholangiocarcinoma
  • Prostate apoptosis response-4
  • Therapy

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