Modulating cancer cell survival by targeting intracellular cholesterol transport
Modulating cancer cell survival by targeting intracellular cholesterol transport
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DOI：
10.1038/bjc.2017.200
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发表时间：
2017-08-08
影响因子：
8.8
通讯作者：
Robertson, Gavin P.
中科院分区：
文献类型：
--
作者：
Kuzu, Omer F.;Gowda, Raghavendra;Robertson, Gavin P.
背景资料：某些癌症对胆固醇的需求很高，使其对靶向细胞胆固醇稳态的治疗策略可能敏感。一种潜在的方法涉及细胞内胆固醇转运的破坏，这在尼曼-皮克病中由于酸性鞘磷脂酶（ASM）缺乏而发生。因此，一类lysosomotropic化合物，被确定为功能性ASM抑制剂（FIASMAs）可能会表现出化疗活性，通过破坏癌细胞胆固醇homoeostasis.Methods：在这里，化疗效用的ASM抑制进行了研究。研究了FIASMAs对细胞内胆固醇水平、胆固醇稳态、细胞内吞作用和信号级联的影响。ASM抑制的体内疗效证明使用黑色素瘤异种移植物和纳米颗粒制剂的开发，以克服doselimiting CNS相关的副作用的某些FIASMAs.Results：功能性ASM抑制剂抑制细胞内胆固醇转运导致自噬通量，细胞内吞作用和受体酪氨酸激酶信号中断。因此，癌细胞赖以生存的主要致癌信号级联被抑制。两个测试的ASM抑制剂，奋乃静和氟奋乃静，也是临床上用作抗精神病药，有效地抑制异种移植肿瘤的生长。纳米脂质体封装的奋乃静增强其化疗效果，同时减少CNS相关的副作用。结论：这项研究表明，细胞内胆固醇转运的破坏，靶向ASM可以被利用作为一个潜在的化疗方法治疗癌症。
Background: Demand for cholesterol is high in certain cancers making them potentially sensitive to therapeutic strategies targeting cellular cholesterol homoeostasis. A potential approach involves disruption of intracellular cholesterol transport, which occurs in Niemann-Pick disease as a result of acid sphingomyelinase (ASM) deficiency. Hence, a class of lysosomotropic compounds that were identified as functional ASM inhibitors (FIASMAs) might exhibit chemotherapeutic activity by disrupting cancer cell cholesterol homoeostasis.Methods: Here, the chemotherapeutic utility of ASM inhibition was investigated. The effect of FIASMAs on intracellular cholesterol levels, cholesterol homoeostasis, cellular endocytosis and signalling cascades were investigated. The in vivo efficacy of ASM inhibition was demonstrated using melanoma xenografts and a nanoparticle formulation was developed to overcome doselimiting CNS-associated side effects of certain FIASMAs.Results: Functional ASM inhibitors inhibited intracellular cholesterol transport leading to disruption of autophagic flux, cellular endocytosis and receptor tyrosine kinase signalling. Consequently, major oncogenic signalling cascades on which cancer cells were reliant for survival were inhibited. Two tested ASM inhibitors, perphenazine and fluphenazine that are also clinically used as antipsychotics, were effective in inhibiting xenografted tumour growth. Nanoliposomal encapsulation of the perphenazine enhanced its chemotherapeutic efficacy while decreasing CNS-associated side effects.Conclusions: This study suggests that disruption of intracellular cholesterol transport by targeting ASM could be utilised as a potential chemotherapeutic approach for treating cancer.