Expression level of Bcl-XL critically affects sensitivity of hepatocellular carcinoma cells to LIGHT-enhanced and interferon-gamma-induced apoptosis.
The molecular mechanisms of apoptosis caused by IFN-gamma (interferon gamma)/LIGHT (lymphotoxin-related inducible ligand that competes for glycoprotein D binding to herpes virus entry mediator on T cells) have not been studied in detail. The present study was undertaken to gain insights into the signaling pathways involved in apoptosis induced by IFN-gamma/LIGHT in hepatocellular carcinoma (HCC) cell lines. Cell proliferation assay, flow cytometry, Western blotting, gene transfer and RNA interference were used in this study. LIGHT enhanced IFN-gamma-mediated apoptosis in Hep3B cells. IFN-gamma/LIGHT-induced apoptosis was inhibited by blocking peptides to the lymphotoxin beta receptor (LT-beta R), and not by the herpes virus entry mediator (HVEM). Expression of LT-beta R remained unchanged after cytokine treatments. IFN-gamma/LIGHT treatment resulted in the down-regulation of Bcl-XL and the activation of caspase-9 and caspase-3 as well as the decrease of phosphorylation of STAT3. HepG2 and SMMC-7721 cells, which showed high levels of endogenous Bcl-XL, displayed resistance to IFN-gamma/LIGHT-induced apoptosis. Overexpression of Bcl-XL in Hep3B cells increased the resistance to IFN-gamma/LIGHT induced apoptosis while the down-regulation of Bcl-XL in HepG2 and SMMC-7721 cells by RNA interference decreased the resistance. Our study provides important mechanistic insights into IFN-gamma/LIGHT- induced apoptosis in HCC cells and may help to select better therapeutic strategies for certain cancers with distinct Bcl-XL expression.
Li
Jun
J
Division of Comprehensive Treatment, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai 200438, PR China.
Shen
Feng
F
Wu
Dong
D
Wei
Li-Xin
LX
Wang
Yi-Zhen
YZ
Shi
Le-Hua
LH
Zou
Ying
Y
Wu
Meng-Chao
MC
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D053259:Lymphotoxin beta Receptor / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D051020:bcl-X Protein / Q000096:biosynthesis* / Q000235:genetics
D053259:Lymphotoxin beta Receptor; D034741:RNA, Small Interfering; D053240:Receptors, Tumor Necrosis Factor, Member 14; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D051020:bcl-X Protein; D007371:Interferon-gamma