A chenodeoxycholic derivative, HS-1200, induces apoptosis and cell cycle modulation via Egr-1 gene expression control on human hepatoma cells.
We previously reported that HS-1200, a synthetic chenodeoxycholic acid derivative, has apoptosis-inducing activity in various human cancer cells. The present study was undertaken to examine whether HS-1200 had an anticancer effect on HepG2 (wild-type p53) and Hep3B (p53 deleted) human hepatoma cells. Treatment of both cells with HS-1200 resulted in growth inhibition and induction of apoptosis as measured by MTT assay, nuclear staining, DNA fragmentation and flow cytometry analysis. The increase in apoptosis was associated with the alteration in the ratio of Bcl-2/Bax protein expression. In addition, flow cytometry analysis indicated that HS-1200 induced G1 phase arrest in both cells. When analyzing the expression of cell cycle-related proteins, we found that HS-1200 reduced the expression levels of cyclin D1, cyclin A, and Cdk2. HS-1200 treatment also caused an increase in the expression levels of p21 WAF1/CIP1 in HepG2 cells in a p53-dependent manner and in Hep3B cells in a p53-independent manner. Moreover, the expression level of p27 KIP1 was increased in both cell lines. We also observed that HS-1200 decreased the levels of cyclooxygenase (COX)-2 mRNA and protein expression. Furthermore, HS-1200 treatment markedly induced the Egr-1 expression at an early time point, and the increased expression levels of p53, p21 WAF1/CIP1, p27 KIP1, and COX-2 after treatment with HS-1200 were completely inhibited in HepG2 cells and partially inhibited in Hep3B cells by silencing of Egr-1, respectively. Taken together, these findings provide important new insights into the possible molecular mechanisms of the anticancer activity of the synthetic bile acid derivative, HS-1200, through Egr-1 regulation.
Park
Sang Eun
SE
Department of Pharmacy BK21 Program, Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea.
Lee
Sun Wha
SW
Hossain
Mohammad Akbar
MA
Kim
Min Young
MY
Kim
Mi-Na
MN
Ahn
Eun Young
EY
Park
Young Chul
YC
Suh
Hongsuk
H
Kim
Gi-Young
GY
Choi
Yung Hyun
YH
Kim
Nam Deuk
ND
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002635:Chenodeoxycholic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000502:physiology; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051546:Cyclooxygenase 2 / Q000502:physiology; D051766:Early Growth Response Protein 1 / Q000235:genetics* / Q000502:physiology; D016193:G1 Phase / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; C436291:CDKN1B protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C479128:HS 1200; D047908:Intracellular Signaling Peptides and Proteins; D016159:Tumor Suppressor Protein p53; D002635:Chenodeoxycholic Acid; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051546:Cyclooxygenase 2