BAD, a proapoptotic member of the BCL2 family, is a potential therapeutic target in hepatocellular carcinoma.
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.
Galmiche
Antoine
A
Laboratoire de Biochimie, CHU Nord, Amiens Cedex, France. Galmiche.Antoine@chu-amiens.fr
Ezzoukhry
Zakaria
Z
François
Catherine
C
Louandre
Christophe
C
Sabbagh
Charles
C
Nguyen-Khac
Eric
E
Descamps
Véronique
V
Trouillet
Nathalie
N
Godin
Corinne
C
Regimbeau
Jean-Marc
JM
Joly
Jean-Paul
JP
Barbare
Jean-Claude
JC
Duverlie
Gilles
G
Mazière
Jean-Claude
JC
Chatelain
Denis
D
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
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