Growth inhibition and gene induction in human hepatocellular carcinoma cell exposed to sodium 4-phenylbutanoate.
BACKGROUND
Sodium 4-phenylbutanoate (NaPB) can induce cellular differentiation and cell cycle arrest. However, its potential anticancer properties in hepatocellular carcinoma and influence on normal liver cell are still unclear. We observed the effects of NaPB on growth inhibition, including differentiation and phase growth arrest in normal liver cell line L-02 and hepatocellular carcinoma cell line Bel-7402. Furthermore, we investigated its mechanism in Bel-7402. METHODS; Hepatocellular carcinoma cells Bel-7402 and normal liver cell line L-02 were treated with NaPB at different concentrations. Light microscopy was used to find morphological change in cells. Cell cycle was detected by flow cytometry. Expression of acetylating histone H4 and of histones deacetylase 4 (HDAC4) were determined by Western blot. The expression of P21WAF1/CIP1 and E-cadherin were observed through immunocytochemistry.


RESULTS
NaPB treatment led to time dependent growth inhibition in hepatocellular carcinoma cells Bel-7402. NaPB treatment caused a significant decline in the fraction of S phase cells and a significant increase in G0/G1 cells. NaPB increased the expression of P21(WAF1/CIP1) and E-cadherin in Bel-7402 and significantly decreased the level of HDAC4 in Bel-7402. NaPB significantly improved the level of acetylating histone H4. The normal liver cell line L-02 showed no distinct changes under treatment with NaPB.


CONCLUSIONS
NaPB inhibited the growth of hepatocellular carcinoma cells Bel-7402 and induced partial differentiation through enhancing the acetylating histones. In Bel-7402, the expressions of P21(WAF1/CIP1) and E-cadherin may be related to level of acetylating histones and inhibition of cellular growth. NaPB showed no significant effect on normal liver cells.
Wang
Chun-Ting
CT
Department of Medical Intensive Care Unit, Shandong Province Hospital, Affiliated Hospital of Shandong University, Jinan, Shandong 250021, China.
Meng
Mei
M
Zhang
Ji-Cheng
JC
Jin
Chang-Jun
CJ
Jiang
Jin-Jiao
JJ
Ren
Hong-Sheng
HS
Jiang
Jun-Mei
JM
Qin
Cheng-Yong
CY
Yu
Dong-Qing
DQ
D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D015820:Cadherins / Q000032:analysis; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000032:analysis; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010654:Phenylbutyrates / Q000494:pharmacology*
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D015820:Cadherins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D010654:Phenylbutyrates; C075773:4-phenylbutyric acid