Ceramide toxicity and metabolism differ in wild-type and multidrug-resistant cancer cells.
Ceramide toxicity and metabolism differ in wild-type and multidrug-resistant cancer cells.
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野生型和多重耐药癌细胞中的神经酰胺毒性和代谢有所不同。
DOI：
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发表时间：
1999
影响因子：
5.2
通讯作者：
M. Cabot
中科院分区：
文献类型：
--
作者：
A. Lucci;A. Giuliano;T. Han;T. Dinur;Y. Y. Liu;A. Senchenkov;M. Cabot
以前我们证明，多药耐药（MDR）癌细胞具有升高水平的糖基化形式的神经酰胺，葡萄糖神经酰胺。在这里，我们比较了MCF-7和阿霉素耐药（MCF-7-AdrR）人乳腺癌细胞中的神经酰胺代谢和神经酰胺毒性。MCF-7-AdrR细胞对C6-神经酰胺（1-10 μ M）有抗性;然而，在用C6-神经酰胺处理的MCF-7细胞中，活力急剧下降。神经酰胺，当补充，不代谢的MCF-7细胞。相反，神经酰胺被MCF-7-AdrR细胞有效地转化为葡糖神经酰胺。放射性标记细胞中细胞外[3 H]神经酰胺的分析表明，与MCF-7细胞相比，MCF-7-AdrR细胞外排神经酰胺的能力没有增强。已知的耐药性调节剂三苯乙烯类抗雌激素是神经酰胺转化为葡萄糖神经酰胺的有效抑制剂，表明阻断神经酰胺代谢在化学增敏中起作用。抗孕激素RU 486也阻断了细胞中葡萄糖神经酰胺的合成;然而，雷洛昔芬类似物LY 117018没有影响。我们认为，在MCF-7-AdrR细胞中证明的增强的糖基化神经酰胺的能力是耐药性的分子决定因素，特别是关于对神经酰胺增强剂如蒽环类药物、电离辐射和肿瘤坏死因子-α的耐药性。
Previously we demonstrated that multidrug-resistant (MDR) cancer cells have elevated levels of a glycosylated form of ceramide, glucosylceramide. Here we compared ceramide metabolism and ceramide toxicity in MCF-7 and in adriamycin-resistant (MCF-7-AdrR) human breast cancer cells. MCF-7-AdrR cells were resistant to C6-ceramide (1-10 microM); however, in MCF-7 cells treated with C6-ceramide, viability dropped sharply. Ceramide, when supplemented, was not metabolized by MCF-7 cells. In contrast, ceramide was efficiently converted to glucosylceramide by MCF-7-AdrR cells. Analysis of extracellular [3H]ceramide in radiolabeled cells showed that MCF-7-AdrR cells do not have an enhanced capacity to efflux ceramide compared with MCF-7 cells. Triphenylethylene anti-estrogens, known modulators of drug resistance, were effective inhibitors of ceramide conversion to glucosylceramide, suggesting that blocking ceramide metabolism plays a role in chemosensitization. The anti-progestine, RU486, also blocked glucosylceramide synthesis in cells; however, LY117018, a raloxifene analog, was without influence. We propose that an enhanced capacity to glycosylate ceramide as evidenced in MCF-7-AdrR cells, is a molecular determinant of drug resistance, particularly as regards resistance to ceramide-enhancing agents such as anthracyclines, ionizing radiation, and tumor necrosis factor-alpha.
DOI：
10.1073/pnas.91.1.73
发表时间：
1994-01-04
影响因子：
11.1
作者：
JARVIS, WD;KOLESNICK, RN;GRANT, S
通讯作者：
GRANT, S