Sodium butyrate enhances Fas-mediated apoptosis of human hepatoma cells.
OBJECTIVE
Human hepatoma cells have been reported to be resistant to Fas-mediated apoptosis. Sodium butyrate (SB) induced apoptosis of several cancer cells. We investigated the effects of SB on Fas-mediated apoptosis of hepatoma cells.


METHODS
In hepatoma cells (HuH-6, HuH-7, Hep-G2, and PLC/PRF/5), susceptibility to Fas-mediated apoptosis and Fas expression were assessed. Caspase-3 activation and cell cycle progression were evaluated in HuH-6. A cDNA microarray assay was performed to screen the changes in the expression of mRNAs.


RESULTS
Pretreatment with SB caused an enhancement of the sensitivity to anti-Fas-mediated cytotoxicity, though it did not increase the expression of Fas. The cDNA microarray assay revealed up-regulation of pro-apoptotic Bik, Bak, Bid and c-Jun N-terminal protein kinase-1, and down-regulation of anti-apoptotic Bag-1 and cellular Fas-associated death domain-like interleukin-1beta-converting enzyme inhibitor protein. In some molecules, expression of the proteins was confirmed by Western blotting. An increase in truncated-Bid accompanying the reduction in Bid was also observed.


CONCLUSIONS
SB enhances the susceptibility of hepatoma cells to anti-Fas-mediated cytotoxicity by altering the mRNA and protein expression and/or the activation status of proteins that could be involved in the Fas signaling pathway. SB may have an important role in the elimination of hepatoma cells.
Ogawa
Kohei
K
Third Department of Internal Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0152, Japan.
Yasumura
Satoshi
S
Atarashi
Yoshinari
Y
Minemura
Masami
M
Miyazaki
Takako
T
Iwamoto
Masaya
M
Higuchi
Kiyohiro
K
Watanabe
Akiharu
A
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002087:Butyrates / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D008113:Liver Neoplasms; D020411:Oligonucleotide Array Sequence Analysis; D019014:fas Receptor / Q000378:metabolism*
D002087:Butyrates; D056572:Histone Deacetylase Inhibitors; D019014:fas Receptor