High PPT1 expression predicts poor clinical outcome and PPT1 inhibitor DC661 enhances sorafenib sensitivity in hepatocellular carcinoma

Abstract

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.

Holliday Cross-Recognition Protein HJURP: Association With the Tumor Microenvironment in Hepatocellular Carcinoma and With Patient Prognosis

“…All three of these genes have previously been linked to cancer. PPT1 can promote tumor growth and has already shown prognostic potential on its own in various cancer and HCC (43,44). Downregulating PPT1 can improve the efficacy of ICIs (45).…”

Enhancing Anti-Cancer Therapy with Selective Autophagy Inhibitors by Targeting Protective Autophagy

“…Besides these inhibitors, bafilomycin A1, ROC-325, LS-1-10, BRD1240, cytochalasin E, Lys05, and DC661 can also inhibit autolysosome formation during autophagic process. Bafilomycin A1, ROC-325, LS-1-10, BRD1240, cytochalasin E, Lys05, and DC661 compounds can inhibit autolysosome formation by elevating lysosomal pH ( Yamamoto et al ., 1998 ; McAfee et al ., 2012 ; Aldrich et al ., 2015 ; Carew et al ., 2017 ; Fu et al ., 2017 ; Takanezawa et al ., 2018 ; Zhou et al ., 2020 ; Xu et al ., 2022 ). DC661 is a dimeric CQ derivative ( Xu et al ., 2022 ).…”

“…Bafilomycin A1, ROC-325, LS-1-10, BRD1240, cytochalasin E, Lys05, and DC661 compounds can inhibit autolysosome formation by elevating lysosomal pH ( Yamamoto et al ., 1998 ; McAfee et al ., 2012 ; Aldrich et al ., 2015 ; Carew et al ., 2017 ; Fu et al ., 2017 ; Takanezawa et al ., 2018 ; Zhou et al ., 2020 ; Xu et al ., 2022 ). DC661 is a dimeric CQ derivative ( Xu et al ., 2022 ). ROC-325, LS-1-10, Lys05, and DC661 have been tested as possible cancer therapeutics in pre-clinical animal models.…”

“…ROC-325, LS-1-10, Lys05, and DC661 have been tested as possible cancer therapeutics in pre-clinical animal models. It was found that they could suppress tumor growth in several cancer models ( McAfee et al ., 2012 ; Carew et al ., 2017 ; Fu et al ., 2017 ; Nawrocki et al ., 2019 ; Rebecca et al ., 2019 ; Xu et al ., 2022 ). ROC-325 and DC661 have a survival benefit in MV4-11 acute myeloid leukemia or Hep1-6 hepatocellular carcinoma (HCC) xenografted mice ( Nawrocki et al ., 2019 ; Xu et al ., 2022 ).…”

Development and validation of a novel cellular senescence-related prognostic signature for predicting the survival and immune landscape in hepatocellular carcinoma

“…Moreover, the Sankey diagram showed that the three srlncRNAs were associated with a few coding genes, including PPT1, PTGDS, and ELOVL1. High PPT1 expression is Frontiers in Genetics frontiersin.org associated with poor prognosis in patients with HCC, and PPT1 inhibition could enhance the sensitivity to sorafenib therapy in HCC (Xu et al, 2022). PTGDs are prognostic biomarkers of breast cancer (Adekeye et al, 2022).…”