Mechanistic study on growth suppression and apoptosis induction by targeting hepatoma-derived growth factor in human hepatocellular carcinoma HepG2 cells.

Abstract

Hepatoma-derived growth factor (HDGF) is frequently overexpressed in human cancer. The growth factor was previously demonstrated to be a survival factor as knock-down of HDGF suppresses the growth and induces apoptosis in human cancer cells through the Bad-mediated intrinsic apoptotic pathway. However, inactivation of Bad cannot completely repress the apoptosis induced upon HDGF knock-down, indicating the presence of other unidentified pathways. In the present study, HDGF knock-down was shown to trigger the Fas-mediated extrinsic apoptotic pathway in human hepatocellular carcinoma HepG2 cells through NF-kappaB signaling pathway. Increases in Fas expression and fas promoter activity were detected upon HDGF knock-down by Western blot analysis and luciferase reporter assay. Knock-down of fas inhibited HDGF knock-down effect on apoptosis induction and growth suppression as revealed by annexin V binding assay and soft agar assay. Down-regulation of IkappaBalpha was also observed upon HDGF knock-down. Overexpression of IkappaBalpha by transient transfection or inhibition of NF-kappaB by BAY11-7082 suppressed HDGF knock-down effect on fas promoter activation, Fas up-regulation, apoptosis induction and growth suppression. Furthermore, the interaction of Fas-mediated extrinsic and Bad-mediated intrinsic apoptotic pathways was demonstrated as a stronger inhibition on apoptosis induction and growth suppression upon HDGF knock-down was observed when both pathways were inactivated. The results therefore suggested that, through both intrinsic and extrinsic apoptotic pathways, HDGF may function as a survival factor and be a potential target for cancer therapy.

• Authors: Tsun Yee Tsang, Wan Yee Tang, Wing Pui Tsang, Ngai Na Co, Siu Kai Kong, Tim Tak Kwok
• Journal: Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology (Cell Physiol Biochem) Vol. 24 Issue 3-4 Pg. 253-62 ( 2009) ISSN: 1421-9778 [Electronic] Germany
• PMID: 19710540 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright (c) 2009 S. Karger AG, Basel.

Chemical References

• 3-(4-methylphenylsulfonyl)-2-propenenitrile
• Annexin A5
• Intercellular Signaling Peptides and Proteins
• NF-kappa B
• Nitriles
• Oligonucleotides, Antisense
• RNA, Small Interfering
• Sulfones
• bcl-Associated Death Protein
• fas Receptor
• hepatoma-derived growth factor
• Luciferases, Renilla

Topics

• Annexin A5 (analysis, metabolism)
• Apoptosis
• Carcinoma, Hepatocellular (genetics, metabolism, pathology)
• Cell Line, Tumor
• DNA Fragmentation (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Genes, Reporter
• Humans
• Intercellular Signaling Peptides and Proteins (genetics)
• Liver Neoplasms (genetics, metabolism, pathology)
• Luciferases, Renilla (metabolism)
• Models, Biological
• NF-kappa B (antagonists & inhibitors, metabolism)
• Nitriles (pharmacology)
• Oligonucleotides, Antisense (pharmacology)
• RNA, Small Interfering (metabolism)
• Signal Transduction
• Sulfones (pharmacology)
• Transfection
• bcl-Associated Death Protein (metabolism)
• fas Receptor (biosynthesis)