Overexpression of sphingosine-1-phosphate lyase or inhibition of sphingosine kinase in Dictyostelium discoideum results in a selective increase in sensitivity to platinum-based chemotherapy drugs.
Overexpression of sphingosine-1-phosphate lyase or inhibition of sphingosine kinase in Dictyostelium discoideum results in a selective increase in sensitivity to platinum-based chemotherapy drugs.
复制标题
盘基网柄菌中 1-磷酸鞘氨醇裂解酶的过度表达或鞘氨醇激酶的抑制导致对铂类化疗药物的敏感性选择性增加。
DOI：
10.1128/ec.3.3.795-805.2004
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Alexander,Stephen
中科院分区：
文献类型：
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作者：
Min,Junxia;Stegner,AndrewL;Alexander,Hannah;Alexander,Stephen
化疗药物顺铂的疗效往往由于肿瘤对药物的耐药性而受到限制，增加顺铂的效力而不增加其浓度可能是有益的。先前发现的一种对顺铂耐药性增加的盘状盘状钢突菌突变体在编码鞘氨醇-1-磷酸（S-1-P）裂解酶的基因上存在缺陷，该酶催化S-1-P的分解，而S-1-P是细胞功能和发育以及细胞命运的重要调节分子。我们假设顺铂耐药性的增加是由于S-1-P的升高，并预测S-1-P水平的降低应该会增加对药物的敏感性。我们产生了三株稳定过表达不同水平S-1-P裂解酶的菌株。过表达菌株的生长速度降低，证实了这一假设，显示出对顺铂敏感性的表达依赖性增加。与此一致的是，用已知的鞘氨醇激酶抑制剂-红-N，N，-二甲基鞘氨醇处理细胞，增加突变细胞和亲本细胞对顺铂的敏感性，而添加外源性S-1-P或8- br -环AMP使细胞对顺铂更具抗性。对于顺铂类似物卡铂，也观察到过表达者对顺铂的敏感性增加。相比之下，对阿霉素、5-氟尿嘧啶或依托泊苷的反应不受影响，这表明鞘脂代谢途径参与调节对顺铂的反应并不是全局遗传毒性应激反应的一部分。对顺铂的敏感性增强似乎是S-1-P细胞内信号功能的结果，因为。盘状瘤似乎没有内皮分化生长（EDG/S1P）受体。总之，研究结果表明，多点调节鞘脂通路可导致对顺铂的敏感性增加，并有可能增加这种重要药物的临床应用。
The efficacy of the chemotherapy drug cisplatin is often limited due to resistance of the tumors to the drug, and increasing the potency of cisplatin without increasing its concentration could prove beneficial. A previously characterizedDictyostelium discoideummutant with increased resistance to cisplatin was defective in the gene encoding sphingosine-1-phosphate (S-1-P) lyase, which catalyzes the breakdown of S-1-P, an important regulatory molecule in cell function and development and in the regulation of cell fate. We hypothesized that the increased resistance to cisplatin was due to an elevation of S-1-P and predicted that lowering levels of S-1-P should increase sensitivity to the drug. We generated three strains that stably overexpress different levels of the S-1-P lyase. The overexpressor strains have reduced growth rate and, confirming the hypothesis, showed an expression-dependent increase in sensitivity to cisplatin. Consistently, treating the cells withd-erythro-N,N,-dimethylsphingosine, a known inhibitor of sphingosine kinase, increased the sensitivity of mutant and parent cells to cisplatin, while addition of exogenous S-1-P or 8-Br-cyclic AMP made the cells more resistant to cisplatin. The increased sensitivity of the overexpressors to cisplatin was also observed with the cisplatin analog carboplatin. In contrast, the response to doxorubicin, 5-flurouracil, or etoposide was unaffected, indicating that the involvement of the sphingolipid metabolic pathway in modulating the response to cisplatin is not part of a global genotoxic stress response. The augmented sensitivity to cisplatin appears to be the result of an intracellular signaling function of S-1-P, becauseD. discoideumdoes not appear to have endothelial differentiation growth (EDG/S1P) receptors. Overall, the results show that modulation of the sphingolipid pathway at multiple points can result in increased sensitivity to cisplatin and has the potential for increasing the clinical usefulness of this important drug.