PPT1 Promotes Tumor Growth and Is the Molecular Target of Chloroquine Derivatives in Cancer
PPT1 Promotes Tumor Growth and Is the Molecular Target of Chloroquine Derivatives in Cancer
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DOI：
10.1158/2159-8290.cd-18-0706
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发表时间：
2019-02-01
期刊：
影响因子：
28.2
通讯作者：
Amaravadi, Ravi K.
中科院分区：
文献类型：
--
作者：
Rebecca, Vito W.;Nicastri, Michael C.;Amaravadi, Ravi K.
将亲溶酶体氯喹（CQ）衍生物重新用作癌症自噬抑制剂的临床试验显示出令人鼓舞的结果，但其潜在的作用机制仍不清楚。在这里，我们报告了一种新的二聚体CQ（DC 661）能够去酸化的溶酶体和抑制自噬显着优于羟氯喹（HCQ）。使用原位光亲和下拉策略，我们将棕榈酰蛋白硫酯酶1（PPT 1）鉴定为单体和二聚体CQ衍生物共有的分子靶点。HCQ和Lys 05也结合并抑制PPT 1活性，但只有DC 661在酸性介质中保持活性。使用CRISPR/Cas9编辑敲除癌细胞中的PPT 1消除了CQ衍生物的自噬调节和细胞毒性，并导致与用DC 661观察到的类似的肿瘤生长的显著损害。PPT 1在肿瘤中的高表达与多种癌症患者的生存率低相关。因此，PPT 1代表了一个新的目标，在癌症中，可以被抑制与CQ derivatives.SIGNIFICANCE：这项研究确定PPT 1作为以前未知的溶酶体分子靶的单体和二聚体CQ衍生物。PPT 1的遗传抑制损害肿瘤生长，并且PPT 1水平在癌症中升高并与生存率低相关。这些发现为在癌症中靶向PPT 1提供了强有力的理论基础。
Clinical trials repurposing lysosomotropic chloroquine (CQ) derivatives as autophagy inhibitors in cancer demonstrate encouraging results, but the underlying mechanism of action remains unknown. Here, we report a novel dimeric CQ (DC661) capable of deacidifying the lysosome and inhibiting autophagy significantly better than hydroxychloroquine (HCQ). Using an in situ photoaffinity pulldown strategy, we identified palmitoyl-protein thioesterase 1 (PPT1) as a molecular target shared across monomeric and dimeric CQ derivatives. HCQ and Lys05 also bound to and inhibited PPT1 activity, but only DC661 maintained activity in acidic media. Knockout of PPT1 in cancer cells using CRISPR/Cas9 editing abrogates autophagy modulation and cytotoxicity of CQ derivatives, and results in significant impairment of tumor growth similar to that observed with DC661. Elevated expression of PPT1 in tumors correlates with poor survival in patients in a variety of cancers. Thus, PPT1 represents a new target in cancer that can be inhibited with CQ derivatives.SIGNIFICANCE: This study identifies PPT1 as the previously unknown lysosomal molecular target of monomeric and dimeric CQ derivatives. Genetic suppression of PPT1 impairs tumor growth, and PPT1 levels are elevated in cancer and associated with poor survival. These findings provide a strong rationale for targeting PPT1 in cancer.