High PPT1 expression predicts poor clinical outcome and PPT1 inhibitor DC661 enhances sorafenib sensitivity in hepatocellular carcinoma.
High PPT1 expression predicts poor clinical outcome and PPT1 inhibitor DC661 enhances sorafenib sensitivity in hepatocellular carcinoma.
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高 PPT1 表达预示较差的临床结果，PPT1 抑制剂 DC661 增强索拉非尼在肝细胞癌中的敏感性
DOI：
10.1186/s12935-022-02508-y
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发表时间：
2022-03-11
影响因子：
5.8
通讯作者：
Zheng Q
中科院分区：
文献类型：
--
作者：
Xu J;Su Z;Cheng X;Hu S;Wang W;Zou T;Zhou X;Song Z;Xia Y;Gao Y;Zheng Q
索拉非尼治疗的适应性耐药和副作用导致肝细胞癌（HCC）患者的生存不满意。棕榈酰蛋白硫酯酶1 （PPT1）在各种癌症的进展中起着关键作用。然而，其在HCC预后和免疫浸润中的作用尚不清楚。通过对Cancer Genome Atlas数据库的数据挖掘，初步研究了PPT1在HCC中的作用。此外，肝癌细胞系Hep 3B和Hep 1-6用DC661或siRNA对抗PPT1。体外通过CCK-8试验、集落形成试验、TUNEL染色、免疫荧光染色、Western blot试验、PI-Annexin V凋亡试验检测PPT1的生物学功能。采用皮下注射动物模型研究靶向PPT1的治疗作用。我们发现，与正常组织相比，PPT1水平在HCC组织中显著上调，并与预后不良显著相关。多因素分析进一步证实PPT1的高表达是HCC患者总生存率差的独立危险因素。我们最初发现PPT1在本研究中建立的索拉非尼耐药细胞系中显著上调。索拉非尼治疗后，HCC细胞通过诱导自噬获得适应性耐药。我们发现DC661，一种选择性和有效的小分子ppt1抑制剂，诱导溶酶体膜通透性，导致溶酶体脱酸，抑制自噬，增强HCC细胞索拉非尼敏感性。有趣的是，这种增敏效应也是通过诱导线粒体通路凋亡介导的。此外，PPT1的表达水平与HCC肿瘤微环境中的免疫浸润有关，PPT1抑制剂DC661通过促进树突状细胞成熟，进而促进CD8+ T细胞活化，显著增强抗肿瘤免疫应答。此外，DC661联合索拉非尼治疗免疫小鼠肿瘤模型也非常有效。我们的研究结果表明，用DC661联合索拉非尼靶向PPT1可能是一种新的有效的HCC替代治疗策略。在线版本包含补充材料，可在10.1186/s12935-022-02508-y获得。
Adaptive resistance and side effects of sorafenib treatment result in unsatisfied survival of patients with hepatocellular carcinoma (HCC). Palmitoyl-protein thioesterase 1 (PPT1) plays a critical role in progression of various cancers. However, its role on prognosis and immune infiltrates in HCC remains unclarified. By data mining in the Cancer Genome Atlas databases, the role of PPT1 in HCC were initially investigated. Furthermore, HCC cell lines Hep 3B and Hep 1-6 were treated with DC661 or siRNA against PPT1. The biological function of PPT1 was determined by CCK-8 test, colony formation assay, TUNEL staining, immunofluorescence staining, Western blot test, and PI-Annexin V apoptosis assays in vitro. Animal models of subcutaneous injection were applied to investigate the therapeutic role of targeting PPT1. We found that PPT1 levels were significantly upregulated in HCC tissues compared with normal tissues and were significantly associated with a poor prognosis. Multivariate analysis further confirmed that high expression of PPT1 was an independent risk factor for poor overall survival of HCC patients. We initially found that PPT1 was significantly upregulated in sorafenib-resistant cell lines established in this study. Upon sorafenib treatment, HCC cells acquired adaptive resistance by inducing autophagy. We found that DC661, a selective and potent small-molecule PPT1-inhibitor, induced lysosomal membrane permeability, caused lysosomal deacidification, inhibited autophagy and enhanced sorafenib sensitivity in HCC cells. Interestingly, this sensitization effect was also mediated by the induction mitochondrial pathway apoptosis. In addition, the expression level of PPT1 was associated with the immune infiltration in the HCC tumor microenvironment, and PPT1 inhibitor DC661 significantly enhanced the anti-tumor immune response by promoting dendritic cell maturation and further promoting CD8+ T cell activation. Moreover, DC661 combined with sorafenib was also very effective at treating tumor models in immunized mice. Our findings suggest that targeting PPT1 with DC661 in combination with sorafenib might be a novel and effective alternative therapeutic strategy for HCC. The online version contains supplementary material available at 10.1186/s12935-022-02508-y.
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影响因子：
2.1
作者：
Nicastri MC;Rebecca VW;Amaravadi RK;Winkler JD
通讯作者：
Winkler JD
影响因子：
3.7
作者：
Chou SD;Prince T;Gong J;Calderwood SK
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Calderwood SK
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作者：
Bahreyni A;Mohamud Y;Luo H
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Luo H
影响因子：
5.8
作者：
Shuai Y;Fan E;Zhong Q;Chen Q;Feng G;Gou X;Zhang G
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Zhang G
影响因子：
13.3
作者：
Mahalingam, Devalingam;Mita, Monica;Carew, Jennifer S.
通讯作者：
Carew, Jennifer S.