Targeting the sphingolipid metabolism to defeat pancreatic cancer cell resistance to the chemotherapeutic gemcitabine drug
Targeting the sphingolipid metabolism to defeat pancreatic cancer cell resistance to the chemotherapeutic gemcitabine drug
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DOI：
10.1158/1535-7163.mct-08-1096
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发表时间：
2009-04-01
影响因子：
5.7
通讯作者：
Bousquet, Corinne
中科院分区：
文献类型：
--
作者：
Guillermet-Guibert, Julie;Davenne, Lise;Bousquet, Corinne
战胜胰腺癌对化疗药物吉西他滨的耐药性仍然是治疗这种致命癌症的一个挑战。以鞘脂代谢为目标来改善肿瘤化疗敏感性最近已成为一种有前景的策略。促存活的 1-磷酸鞘氨醇 (S1P) 和促凋亡的神经酰胺鞘脂的细胞内水平之间的精细平衡决定了细胞的命运。在控制这种代谢的酶中，鞘氨醇激酶-1 (Sphl 1)（一种在许多癌症中过度表达的肿瘤相关蛋白）通过 S1P 的产生有利于生存，并且 SphK1 抑制剂在正在进行的临床试验中用于使上皮性卵巢癌细胞和前列腺癌细胞对各种化疗药物敏感。我们在此报告，细胞神经酰胺/S1P 比率是预测胰腺癌细胞对吉西他滨敏感性的关键生物传感器。低水平的神经酰胺/S1P 比率与高 SphK1 活性相关，与胰腺癌细胞对吉西他滨的强大内在化学耐药性相关。引人注目的是，通过使用药理学（SphK1 抑制剂或神经酰胺类似物）或基于小干扰 RNA 的方法上调细胞内神经酰胺水平或降低 SphK1 活性来增加神经酰胺/S1P 比率，使胰腺癌细胞对吉西他滨敏感。相反，通过上调 SphK1 活性来降低神经酰胺/S1P 比例，会促进这些细胞对吉西他滨的耐药性。因此，针对鞘脂代谢的新型药理学策略的开发可能代表了一种有趣的有前途的方法，当与吉西他滨联合使用时，可以克服胰腺癌对该药物的化学耐药性。 [摩尔癌症疗法 2009;8(4):809-20]
Defeating pancreatic cancer resistance to the chemotherapeutic drug gemcitabine remains a challenge to treat this deadly cancer. Targeting the sphingolipid metabolism for improving tumor chemosensitivity has recently emerged as a promising strategy. The fine balance between intracellular levels of the prosurvival sphingosine-1-phosphate (S1P) and the proapoptotic ceramide sphingolipids determines cell fate. Among enzymes that control this metabolism, sphingosine kinase-1 (Sphl 1), a tumor-associated protein overexpressed in many cancers, favors survival through S1P production, and inhibitors of SphK1 are used in ongoing clinical trials to sensitize epithelial ovarian and prostate cancer cells to various chemotherapeutic drugs. We here report that the cellular ceramide/S1P ratio is a critical biosensor for predicting pancreatic cancer cell sensitivity to gemcitabine. A low level of the ceramide/S1P ratio, associated with a high SphK1 activity, correlates with a robust intrinsic pancreatic cancer cell chemoresistance toward gemcitabine. Strikingly, increasing the ceramide/S1P ratio, by using pharmacologic (SphK1 inhibitor or ceramide analogue) or small interfering RNA-based approaches to up-regulate intracellular ceramide levels or reduce SphK1 activity, sensitized pancreatic cancer cells to gemcitabine. Conversely, decreasing the ceramide/S1P ratio, by up-regulating SphK1 activity, promoted gemcitabine resistance in these cells. Development of novel pharmacologic strategies targeting the sphingolipid metabolism might therefore represent an interesting promising approach, when combined with gemcitabine, to defeat pancreatic cancer chemoresistance to this drug. [Mol Cancer Ther 2009;8(4):809-20]