Department of Basic Pharmaceutical Sciences, University of Louisiana at Monroe, Monroe, LA, USA.
Adv Cancer Res. 2013;117:59-89. doi: 10.1016/B978-0-12-394274-6.00003-0.
Glucosylceramide synthase (GCS), converting ceramide to glucosylceramide, catalyzes the first reaction of ceramide glycosylation in sphingolipid metabolism. This glycosylation by GCS is a critical step regulating the modulation of cellular activities by controlling ceramide and glycosphingolipids (GSLs). An increase of ceramide in response to stresses, such as chemotherapy, drives cells to proliferation arrest and apoptosis or autophagy; however, ceramide glycosylation promptly eliminates ceramide and consequently, these induced processes, thus protecting cancer cells. Further, persistently enhanced ceramide glycosylation can increase GSLs, participating in selecting cancer cells to drug resistance. GCS is overexpressed in diverse drug-resistant cancer cells and in tumors of breast, colon, and leukemia that display poor response to chemotherapy. As ceramide glycosylation by GCS is a rate-limiting step in GSL synthesis, inhibition of GCS sensitizes cancer cells to anticancer drugs and eradicates cancer stem cells. Mechanistic studies indicate that uncoupling ceramide glycosylation can modulate gene expression, decreasing MDR1 through the cSrc/β-catenin pathway and restoring p53 expression via RNA splicing. These studies not only expand our knowledge in understanding how ceramide glycosylation affects cancer cells but also provide novel therapeutic approaches for targeting refractory tumors.
葡萄糖神经酰胺合酶（GCS）将神经酰胺转化为葡萄糖神经酰胺，催化鞘脂代谢中神经酰胺糖基化的第一个反应。GCS 的这种糖基化是通过控制神经酰胺和糖脂（GSL）来调节细胞活性的调节的关键步骤。应激（如化疗）引起的神经酰胺增加会促使细胞增殖停滞、凋亡或自噬；然而，神经酰胺糖基化会迅速消除神经酰胺，从而消除这些诱导过程，从而保护癌细胞。此外，持续增强的神经酰胺糖基化可以增加 GSL，参与选择对药物有抵抗力的癌细胞。GCS 在多种耐药癌细胞以及对化疗反应不佳的乳腺癌、结肠癌和白血病肿瘤中过度表达。由于 GCS 的神经酰胺糖基化是 GSL 合成的限速步骤，因此抑制 GCS 可使癌细胞对抗癌药物敏感，并根除癌症干细胞。机制研究表明，解偶联神经酰胺糖基化可以调节基因表达，通过 cSrc/β-catenin 途径降低 MDR1，并通过 RNA 剪接恢复 p53 表达。这些研究不仅扩展了我们对神经酰胺糖基化如何影响癌细胞的理解，还为靶向难治性肿瘤提供了新的治疗方法。
