Aneuploid Cell Survival Relies upon Sphingolipid Homeostasis.
Aneuploid Cell Survival Relies upon Sphingolipid Homeostasis.
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非整倍体细胞的存活依赖于鞘脂稳态
DOI：
10.1158/0008-5472.can-17-0049
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发表时间：
2017-10-01
期刊：
影响因子：
11.2
通讯作者：
Amon A
中科院分区：
文献类型：
--
作者：
Tang YC;Yuwen H;Wang K;Bruno PM;Bullock K;Deik A;Santaguida S;Trakala M;Pfau SJ;Zhong N;Huang T;Wang L;Clish CB;Hemann MT;Amon A
非整倍体是癌细胞的一个标志，为癌症治疗和预防策略提供了一个有吸引力的机会。使用基于细胞的筛选来鉴定可以选择性地杀死非整倍体细胞的小分子，我们鉴定了化合物N-[2-羟基-1-（4-吗啉基甲基）-2-苯乙基]-癸酰胺单盐酸盐（DL-PdR），其是UDP-葡萄糖神经酰胺葡萄糖基转移酶的拮抗剂。DL-酪氨酸激酶选择性抑制非整倍体原代小鼠胚胎成纤维细胞和非整倍体结肠直肠癌细胞的增殖。其选择性细胞毒性作用是基于进一步加重神经酰胺水平的升高，神经酰胺是非整倍体细胞的特征，导致细胞凋亡增加。我们观察到，DL-紫杉醇还可以增强紫杉醇的细胞毒性作用，紫杉醇是一种标准的护理化疗剂，在人结肠癌和小鼠淋巴瘤细胞中引起非整倍体。我们的研究结果提供了药理学证据，表明癌细胞中的非整倍体状态可以选择性地用于治疗目的，或用于降低紫杉烷类药物治疗方案的毒性。
Aneuploidy, a hallmark of cancer cells, poses an appealing opportunity for cancer treatment and prevention strategies. Using a cell-based screen to identify small molecules that could selectively kill aneuploid cells, we identified the compound N-[2-hydroxy-1-(4-morpholinylmethyl)-2-phenylethyl]-decanamide monohydrochloride (DL-PDMP), an antagonist of UDP-glucose ceramide glucosyltransferase. DL-PDMP selectively inhibited proliferation of aneuploid primary mouse embryonic fibroblasts and aneuploid colorectal cancer cells. Its selective cytotoxic effects were based on further accentuating the elevated levels of ceramide which characterize aneuploid cells, leading to increased apoptosis. We observed that DL-PDMP could also enhance the cytotoxic effects of paclitaxel, a standard of care chemotherapeutic agent that causes aneuploidy, in human colon cancer and mouse lymphoma cells. Our results offer pharmacological evidence that the aneuploid state in cancer cells can be targeted selectively for therapeutic purposes, or for reducing the toxicity of taxane-based drug regimens.