title: Increasing ceramides sensitizes genistein-induced melanoma cell apoptosis and growth inhibition.
abstract: The aim of the current study is to investigate the effect of ceramides on genistein-induced anti-melanoma effects in vitro. We found that exogenously added cell-permeable short-chain ceramides (C6) dramatically enhanced genistein-induced growth inhibition and apoptosis in cultured melanoma cells. Genistein treatment only induced a moderate intracellular ceramides accumulation in B16 melanoma cells. Two different agents including 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), a ceramide glucosylation inhibitor, and the sphingosine kinase-1 (SphK1) inhibitor II (SKI-II), a sphingosine (ceramides precursor) phosphorylation inhibitor, both facilitated genistein-induced ceramides accumulation and melanoma cell apoptosis. Co-administration of ceramide (C6) and genistein induced a significant Akt inhibition and c-jun-NH(2)-kinase (JNK) activation, caspase-3 cleavage and cytochrome c release. Caspase-3 inhibitor z-DVED-fmk, JNK inhibitor SP 600125, or to restore Akt activation by introducing a constitutively active form of Akt (CA-Akt) diminished ceramide (C6) and genistein co-administration-induced in vitro anti-melanoma effect. Our study suggests that increasing cellular level of ceramides may sensitize genistein-induced anti-melanoma effects.
authors.affiliation: Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210024, Jiangsu, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Ji
authors.forename: Yan-Li
authors.initials: YL
authors.lastname: Yang
authors.forename: Li
authors.initials: L
authors.lastname: He
authors.forename: Bing
authors.initials: B
authors.lastname: Gu
authors.forename: Ji-Ping
authors.initials: JP
authors.lastname: Xia
authors.forename: Wei-Ling
authors.initials: WL
authors.lastname: Sun
authors.forename: Zhong-Lan
authors.initials: ZL
authors.lastname: Su
authors.forename: Bin
authors.initials: B
authors.lastname: Chen
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: Bi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002518:Ceramides / Q000096:biosynthesis / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000096:biosynthesis; D008545:Melanoma / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000473:pathology; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D013844:Thiazoles
chemical_list: C525025:4-(4-(4-chloro-phenyl)thiazol-2-ylamino)phenol; D000970:Antineoplastic Agents; D002518:Ceramides; D009025:Morpholines; D013844:Thiazoles; C101954:N-caproylsphingosine; C033110:RV 538; D019833:Genistein; D048670:MAP Kinase Kinase 4