Increasing ceramides sensitizes genistein-induced melanoma cell apoptosis and growth inhibition

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• 作者：Chao Ji^a ; ¹ ; Yan-li Yang^b ; ¹ ; Li He^c ; Bing Gu^d ; Ji-ping Xia^a ; Wei-ling Sun^a ; Zhong-lan Su^a ; Bin Chen^a ; ^{chenbin3@medmail.com.cn} ; Zhi-gang Bi^e ; ^{eltonbibenqhospital@yahoo.com.cn}
• 关键词：CI ; combination index ; PI ; propidium iodide ; MTT ; 3-(4 ; 5-dimethylthiazol-2-yl)-2 ; 5-diphenyltetrazolium bromide. SKI-II ; SphK1 inhibitor II ; PDMP ; 1-phenyl-2-decanoylamino-3-morpholino-1-propanol ; FACS ; fluorescence-activated cell sorting ; mTOR ; mammalian
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2012
• 期刊代码：159_0006291x
• 类别：bio
• 出版时间：11 May, 2012
• 卷：421
• 期：3
• 页码：462-467
• 文件大小：576 K

摘要

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-NH₂-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.