Bid sensitizes apoptosis induced by chemotherapeutic drugs in hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is one of the most common malignancies in Asia. HCC is often resistant to chemotherapy and the mechanism remains unclear. Mitochondrion-mediated pathway is critical in hepatocyte apoptosis, which suggests Bcl-2 family genes may play a role in the regulation of chemotherapy in HCC. In the present study, we investigated the role of BH3 domain-only protein Bid in HCC tissues, HCC-derived cell lines and how the expression of Bid was related to chemotherapeutic agent-induced apoptosis. Bid was differently expressed in HCC tissues and hepatoma cell lines. Hep3B, a Bid-abundant HCC cell line, was more sensitive to drug-induced cytotoxicity than PLC/PRF/5, a Bid-insufficient HCC cell line. The level of caspase activity induced by 5-fluorouracil (5-FU) was higher in Hep3B than in PLC/PRF/5 and a significant increase in the activity occurred at a rather late stage, after 48 h of the treatment. Similar to the activation of caspase, Bid cleavage and activation was only significant at 72 h after the treatment. Overexpression of Bid or tBid sensitized HCC cells to 5-FU and doxorubicin (Dox) treatments. We further demonstrated that such a sensitive effect could be offset by Bcl-xL, as Bid- or tBid-induced apoptosis was completely blocked by the over-expression of Bcl-xL. These results indicate the level of Bid expression is closely associated with the sensitivity of HCC cells to chemotherapeutic drugs, suggesting that Bid plays an important role in HCC management.
Department of Surgery, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong SAR, China.
Ji
J
Miao
George G
GG
Chen
Suk-Ying
SY
Chun
Ernest C W
EC
Chak
Paul B S
PB
Lai
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008099:Liver / Q000166:cytology / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051020:bcl-X Protein
D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D002352:Carrier Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D020169:Caspases