title: Sulforaphane induces apoptosis in human hepatic cancer cells through inhibition of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase4, mediated by hypoxia inducible factor-1-dependent pathway.
abstract: The anti-cancer activity of sulforaphane (SFN) has recently been investigated in several cancer cell lines, including human hepatic cancers. However, the mechanism of SFN-induced cell death in human hepatic cancer cells is still not well understood. The aim of the present work is to explore the possible mechanisms of SFN-induced apoptosis in hepatocellular carcinoma cells using proteomic analysis. A two-dimensional electrophoresis (2-DE)-based-proteomic analysis was employed for identification of possible target-related proteins of SFN-induced apoptosis. Among eleven proteins identified as regulated, we focused on the down-regulation of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase4 (PFKFB4) protein, which has been known as a key modulator of glycolysis. We also showed that SFN down-regulated the expression of the transcriptional factor, hypoxia inducible factor-1α (HIF-1α), which strongly regulates PFKFB4 expression. In order to obtain a broad understanding of the correlation of HIF-1α and SFN, we observed the inhibition of the activity of mitogen-activated protein kinases, regulators of HIF-1α activity. Our findings suggest that SFN is a potent inducer of apoptosis in hepatocellular carcinoma cells via PFKFB4-inhibition pathways. HIF-1 pathway inhibition may be mediated by the inhibition of mitogen-activated protein kinases.
authors.affiliation: Department of Biological Science, Gachon University of Medicine and Science, Incheon, Republic of Korea.
authors.forename: Young Keul
authors.initials: YK
authors.lastname: Jeon
authors.forename: Dong Ryeol
authors.initials: DR
authors.lastname: Yoo
authors.forename: Yun Ho
authors.initials: YH
authors.lastname: Jang
authors.forename: Se Young
authors.initials: SY
authors.lastname: Jang
authors.forename: Myeong Jin
authors.initials: MJ
authors.lastname: Nam
mesh_terms: D016588:Anticarcinogenic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D055785:Gene Knockdown Techniques; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017879:Isothiocyanates; D008113:Liver Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008954:Models, Biological; D025481:Phosphofructokinase-2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013454:Sulfoxides; D013861:Thiocyanates / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D016588:Anticarcinogenic Agents; D004791:Enzyme Inhibitors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017879:Isothiocyanates; C506672:PFKFB4 protein, human; D034741:RNA, Small Interfering; D013454:Sulfoxides; D013861:Thiocyanates; D025481:Phosphofructokinase-2; C016766:sulforaphane