Gemcitabine kills proliferating endothelial cells exclusively via acid sphingomyelinase activation.
Gemcitabine kills proliferating endothelial cells exclusively via acid sphingomyelinase activation.
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吉西他滨仅通过酸性鞘磷脂酶激活来杀死增殖的内皮细胞。
DOI：
10.1016/j.cellsig.2017.02.021
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发表时间：
2017
影响因子：
4.8
通讯作者：
Kolesnick,Richard
中科院分区：
文献类型：
--
作者：
vanHell,AlbertJ;Haimovitz-Friedman,Adriana;Fuks,Zvi;Tap,WilliamD;Kolesnick,Richard
吉西他滨是一种广泛使用的抗癌药物，在正常和转化的上皮细胞中具有明确的作用机制。然而，其对内皮细胞的影响在很大程度上是未知的。酸性鞘磷脂酶（ASMase）在内皮细胞中高度表达，在各种应激激活后将质膜鞘磷脂转化为促凋亡神经酰胺。在目前的研究中，我们研究了吉西他滨对内皮细胞原代培养的影响。我们发现基线ASMase在牛主动脉内皮细胞（BAEC）中显著增加，因为它们从增殖状态过渡到汇合的生长停滞状态。此外，吉西他滨激活ASMase并诱导分泌型ASMase仅在增殖的内皮细胞中释放到培养基中。此外，增殖性而非生长停滞的BAEC对吉西他滨诱导的凋亡性死亡敏感，这种作用通过用丙咪嗪抑制ASMase或通过用抗神经酰胺Ab结合细胞表面上的神经酰胺来阻断。融合生长停滞的BAEC可以通过提供外源性鞘磷脂酶对吉西他滨诱导的凋亡重新敏感。在人冠状动脉内皮细胞的原代培养物中观察到高度相似的表型。这些发现揭示了吉西他滨在内皮细胞中的细胞毒性的一种先前未被认识的机制，这可能有助于其临床获益，并表明通过药理学调节增殖性肿瘤内皮细胞中的ASMase/神经酰胺信号传导进一步改善其临床疗效的潜力。
Gemcitabine is a widely-used anti-cancer drug with a well-defined mechanism of action in normal and transformed epithelial cells. However, its effect on endothelial cells is largely unknown. Acid sphingomyelinase (ASMase) is highly expressed in endothelial cells, converting plasma membrane sphingomyelin to pro-apoptotic ceramide upon activation by diverse stresses. In the current study, we investigated gemcitabine impact in primary cultures of endothelial cells. We find baseline ASMase increases markedly in bovine aortic endothelial cells (BAEC) as they transit from a proliferative to a confluent growth-arrested state. Further, gemcitabine activates ASMase and induces release of a secretory ASMase form into the media only in proliferating endothelial cells. Additionally, proliferative, but not growth-arrested BAEC, are sensitive to gemcitabine-induced apoptotic death, an effect blocked by inhibiting ASMase with imipramine or by binding ceramide on the cell surface with an anti-ceramide Ab. Confluent growth-arrested BAEC can be re-sensitized to gemcitabine-induced apoptosis by provision of exogenous sphingomyelinase. A highly similar phenotype was observed in primary cultures of human coronary artery endothelial cells. These findings reveal a previously-unrecognized mechanism of gemcitabine cytotoxicity in endothelium that may well contribute to its clinical benefit, and suggest the potential for further improvement of its clinical efficacy via pharmacologic modulation of ASMase/ceramide signaling in proliferative tumor endothelium.