Background/Aims: 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-1β-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.
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- Death and anti-death: tumor resistance to apoptosis.Nat Rev Cancer. 2002; 2: 277-288
- Constitutive and induced expression of APO-1, a new member of the nerve growth factor/tumor necrosis factor receptor superfamily, in normal and neoplastic cells.Lab Invest. 1993; 69: 415-429
- Lethal effect of the anti-Fas antibody in mice.Nature. 1993; 364: 806-809
- Resistance to Fas-mediated apoptosis in human hepatoma cells.Oncogene. 1995; 11: 1157-1164
- Expression of Fas and anti-Fas-mediated apoptosis in human hepatocellular carcinoma cell lines.J Hepatol. 1996; 25: 454-464
- Lymphocyte apoptosis induced by CD95 (Apo-1/Fas) ligand-expressing tumor cells – a mechanism of immune evasion?.Nat Med. 1996; 2: 1361-1366
- The status of Fas and Fas ligand expression can predict recurrence of hepatocellular carcinoma.Br J Cancer. 2000; 82: 1211-1217
- Survivin promotes cell proliferation in human hepatocellular carcinoma.Hepatology. 2000; 31: 1080-1085
- Expression of Fas and Fas-related molecules in human hepatocellular carcinoma.Hum Pathol. 2001; 32: 250-256
- Analysis of in vivo patterns of caspase 3 gene expression in primary hepatocellular carcinoma and its relationship to p21 (WAF1) expression and hepatic apoptosis.World J Gastroenterol. 2000; 6: 356-360
- Histone deacetylases and cancer: causes and therapies.Nat Rev Cancer. 2001; 1: 194-202
- Histone deacetylase inhibitor as new cancer drugs.Curr Opin Oncol. 2001; 13: 477-483
- Histone deacetylase inhibitors in cancer treatment.Anti-Cancer Drugs. 2002; 13: 1-13
- Inhibitors of histone deacetylase arrest cell cycle and induce apoptosis in cervical carcinoma cells circumventing human papillomavirus oncogene expression.Oncogene. 2001; 20: 4768-4776
- Histone deacetylase inhibitors such as sodium butyrate and trichostatin A induce apoptosis through an increase of the bcl-2-related protein Bad.Brain Tumor Pathol. 2001; 18: 109-114
- Inhibition of histone deacetylase activity enhances Fas receptor-mediated apoptosis in leukemic lymphoblasts.Cell Death Differ. 2001; 8: 1014-1021
- Butyrate sensitizes human colon cancer cells to TRAIL-mediated apoptosis.Surgery. 2001; 130: 265-272
- Sodium butyrate induces apoptosis in human renal cell carcinoma cells and synergistically enhances their sensitivity to anti-Fas-mediated cytotoxicity.Int J Oncol. 2000; 17: 1212-1218
- Histone deacetylase inhibitor downregulation of bcl-xl gene expression leads to apoptotic cell death in mesothelioma.Am J Respir Cell Mol Biol. 2001; 25: 562-568
- Reciprocal regulation of α-fetoprotein and albumin gene expression by butyrate in human hepatoma cells.Gastroenterology. 1994; 107: 499-504
- Sodium butyrate enhances STAT 1 expression in PLC/PRF/5 hepatoma cells and augments their responsiveness to interferon-α.Br J Cancer. 1999; 80: 705-710
- Suppression of growth of hepatocellular carcinoma by sodium butyrate in vitro and in vivo.Int J Cancer. 1998; 76: 897-902
- Fas-mediated apoptosis in primary cultured mouse hepatocytes.Exp Cell Res. 1994; 215: 332-337
- Colon carcinoma cells use different mechanisms to escape CD95-mediated apoptosis.Cancer Res. 1998; 58: 526-534
- Bcl-2 related proteins are dramatically induced at the early stage of differentiation in human liver cancer cells by a histone deacetylase inhibitor projecting an anti-apoptotic role during this period.Oncol Rep. 2000; 7: 285-288
- Loss of butyrate-induced apoptosis in human hepatoma cell lines HCC-M and HCC-T having substantial Bcl-2 expression.Hepatology. 1998; 27: 1223-1240
- Alternations of MAPK activities associated with intestinal cell differentiation.Biochem Biophys Res Commun. 2001; 284: 282-288
- Prospective study of chemoprevention of hepatocellular carcinoma with Sho-saiko-to (TJ-9).Cancer. 1995; 76: 743-749
- Prevention of second primary tumors by an acyclic retinoid, polyprenoic acid, in patients with hepatocellular carcinoma.N Engl J Med. 1996; 334: 1561-1567
- Butyrate. Potential role in colon cancer prevention and treatment.Adv Exp Med Biol. 1997; 427: 169-181
- Clinical pharmacology of sodium butyrate in patients with acute leukemia.Eur J Cancer Clin Oncol. 1987; 23: 1283-1287
- Induction of fetal hemoglobin production in subjects with sickle cell anemia by oral sodium phenylbutyrate.Blood. 1994; 84: 339-343
- A phase I dose escalation and bioavailability study of oral sodium phenylbutyrate in patients with refractory solid tumor malignancies.Clin Cancer Res. 2001; 7: 2292-2300
- Modifying histones to tame cancer: clinical development of sodium phenylbutyrate and other histone deacetylase inhibitors.Expert Opin Investig Drugs. 2000; 9: 2923-2934
- Short chain fatty acids in human large intestine, portal, hepatic and venous blood.Gut. 1987; 28: 1221-1227
- Role of butyric acid and its derivatives in the treatment of colorectal cancer and hemoglobinopathies.Life Sci. 1998; 63: 1739-1760
Accepted: September 22, 2003
Received in revised form: September 10, 2003
Received: April 9, 2003
© 2003 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.