title: BAD, a proapoptotic member of the BCL2 family, is a potential therapeutic target in hepatocellular carcinoma.
abstract: Proteins of the BCL2 family are key regulators of apoptosis. Their expression levels are frequently altered in cancers, enabling tumor cells to survive. To gain insight into the pathogenesis of hepatocellular carcinoma (HCC), we performed a comprehensive survey of the expression of the members of the BCL2 family in samples obtained from surgically resected HCCs. Here, we report the occurrence of a new molecular anomaly, consisting of a strong reduction in the expression of the proapoptotic protein BAD in HCC compared with surrounding nontumoral tissue. We investigate the function of BAD in a panel of HCC cell lines. Using gene overexpression and RNA interference, we show that BAD is involved in the cytotoxic effects of sorafenib, a multikinase blocker, which is currently the sole therapeutic drug effective for the treatment of HCC. Finally, we report that ABT-737, a compound that interacts with proteins of the BCL2 family and exhibits a BAD-like reactivity, sensitizes HCC cells toward sorafenib-induced apoptosis. Collectively, our findings indicate that BAD is a key regulator of apoptosis in HCC and an important determinant of HCC cell response to sorafenib.
authors.affiliation: Laboratoire de Biochimie, CHU Nord, Amiens Cedex, France. Galmiche.Antoine@chu-amiens.fr
authors.forename: Antoine
authors.initials: A
authors.lastname: Galmiche
authors.forename: Zakaria
authors.initials: Z
authors.lastname: Ezzoukhry
authors.forename: Catherine
authors.initials: C
authors.lastname: François
authors.forename: Christophe
authors.initials: C
authors.lastname: Louandre
authors.forename: Charles
authors.initials: C
authors.lastname: Sabbagh
authors.forename: Eric
authors.initials: E
authors.lastname: Nguyen-Khac
authors.forename: Véronique
authors.initials: V
authors.lastname: Descamps
authors.forename: Nathalie
authors.initials: N
authors.lastname: Trouillet
authors.forename: Corinne
authors.initials: C
authors.lastname: Godin
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Regimbeau
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Joly
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Barbare
authors.forename: Gilles
authors.initials: G
authors.lastname: Duverlie
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Mazière
authors.forename: Denis
authors.initials: D
authors.lastname: Chatelain
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001557:Benzenesulfonates / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000378:metabolism; D001713:Biphenyl Compounds / Q000494:pharmacology; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D009536:Niacinamide / Q000031:analogs & derivatives; D009596:Nitrophenols / Q000494:pharmacology; D010671:Phenylurea Compounds; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077157:Sorafenib; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: C501332:ABT-737; D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D014408:Biomarkers, Tumor; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010671:Phenylurea Compounds; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; D012333:RNA, Messenger; D013449:Sulfonamides; D009536:Niacinamide; D000077157:Sorafenib