PMID- 35277179 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220322 IS - 1475-2867 (Print) IS - 1475-2867 (Electronic) IS - 1475-2867 (Linking) VI - 22 IP - 1 DP - 2022 Mar 11 TI - High PPT1 expression predicts poor clinical outcome and PPT1 inhibitor DC661 enhances sorafenib sensitivity in hepatocellular carcinoma. PG - 115 LID - 10.1186/s12935-022-02508-y [doi] LID - 115 AB - BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Our findings suggest that targeting PPT1 with DC661 in combination with sorafenib might be a novel and effective alternative therapeutic strategy for HCC. CI - (c) 2022. The Author(s). FAU - Xu, Jianjun AU - Xu J AD - Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1277, Liberation Avenue, Jianghan District, Wuhan, 430022, China. FAU - Su, Zhe AU - Su Z AD - Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1277, Liberation Avenue, Jianghan District, Wuhan, 430022, China. FAU - Cheng, Xiang AU - Cheng X AD - Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. FAU - Hu, Shaobo AU - Hu S AD - Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1277, Liberation Avenue, Jianghan District, Wuhan, 430022, China. FAU - Wang, Wenjie AU - Wang W AD - Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1277, Liberation Avenue, Jianghan District, Wuhan, 430022, China. FAU - Zou, Tianhao AU - Zou T AD - Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1277, Liberation Avenue, Jianghan District, Wuhan, 430022, China. FAU - Zhou, Xing AU - Zhou X AD - Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1277, Liberation Avenue, Jianghan District, Wuhan, 430022, China. FAU - Song, Zifang AU - Song Z AD - Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1277, Liberation Avenue, Jianghan District, Wuhan, 430022, China. FAU - Xia, Yun AU - Xia Y AD - Department of General Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. Xiayun7373@126.com. FAU - Gao, Yang AU - Gao Y AD - Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1277, Liberation Avenue, Jianghan District, Wuhan, 430022, China. hzkjdgy@163.com. FAU - Zheng, Qichang AU - Zheng Q AUID- ORCID: 0000-0003-4570-0863 AD - Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1277, Liberation Avenue, Jianghan District, Wuhan, 430022, China. qc_zheng@hust.edu.cn. LA - eng GR - No.81903173/national natural science foundation of china/ GR - No. 81874231/national natural science foundation of china/ GR - No. 2019CFB729/natural science foundation of hubei province/ GR - No.02.03.2017-331/foundation of union hospital, tongji medical college, huazhong university of science and technology/ PT - Journal Article DEP - 20220311 PL - England TA - Cancer Cell Int JT - Cancer cell international JID - 101139795 PMC - PMC8917761 OTO - NOTNLM OT - Autophagy OT - Hepatocellular carcinoma OT - Immune infiltration OT - Lysosome OT - PPT1 OT - Prognosis OT - Targeted therapy COIS- The authors declare no competing financial interest. EDAT- 2022/03/13 06:00 MHDA- 2022/03/13 06:01 PMCR- 2022/03/11 CRDT- 2022/03/12 05:21 PHST- 2021/07/28 00:00 [received] PHST- 2022/02/02 00:00 [accepted] PHST- 2022/03/12 05:21 [entrez] PHST- 2022/03/13 06:00 [pubmed] PHST- 2022/03/13 06:01 [medline] PHST- 2022/03/11 00:00 [pmc-release] AID - 10.1186/s12935-022-02508-y [pii] AID - 2508 [pii] AID - 10.1186/s12935-022-02508-y [doi] PST - epublish SO - Cancer Cell Int. 2022 Mar 11;22(1):115. doi: 10.1186/s12935-022-02508-y.