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Novel therapeutic features of disulfiram against hepatocellular carcinoma cells with inhibitory effects on a disintegrin and metalloproteinase 10.

ABSTRACT: Our previous genome-wide association study identified the anti-tumor ligand MHC class I polypeptide-related sequence A (MICA) as a susceptibility gene for hepatitis C virus-induced hepatocellular carcinoma (HCC). We subsequently proved that pharmacological restoration of membrane-bound MICA in HCC cells boosted natural killer cell-mediated anti-cancer effects, confirming that a MICA sheddase, a disintegrin and metalloproteinase 10 (ADAM10), is a therapeutic target. We here searched for approved drugs with inhibitory effects on ADAM10 in vitro, and the anti-alcoholism agent, disulfiram, was identified. Disulfiram elevated membrane-bound MICA levels and reduced production of soluble MICA, an immunological decoy, while simultaneously not having unfavorable off-target effects on natural killer cells and normal human hepatocytes. Functional analyses indicated a mode of non-zinc-binding inhibition of ADAM10 by disulfiram, which also suppressed HCC cell migration. These effects of disulfiram against HCC are expected to further the development of novel therapeutic regimens.

SUBMITTER: Goto K

PROVIDER: S-EPMC5922358 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Novel therapeutic features of disulfiram against hepatocellular carcinoma cells with inhibitory effects on a disintegrin and metalloproteinase 10.

Goto Kaku K Arai Jun J Stephanou Anthony A Kato Naoya N

Oncotarget 20180410 27

Our previous genome-wide association study identified the anti-tumor ligand MHC class I polypeptide-related sequence A (<i>MICA</i>) as a susceptibility gene for hepatitis C virus-induced hepatocellular carcinoma (HCC). We subsequently proved that pharmacological restoration of membrane-bound MICA in HCC cells boosted natural killer cell-mediated anti-cancer effects, confirming that a MICA sheddase, a disintegrin and metalloproteinase 10 (ADAM10), is a therapeutic target. We here searched for ap ...[more]

PMID: 29721164

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Project description:Hepatocellular carcinoma (HCC) is a fatal and dominant form of liver cancer that currently has no effective treatment or positive prognosis. In this study, we explored the antitumor effects of cryptotanshinone (CPT) against HCC and the molecular mechanisms underlying these effects using a systems pharmacology and experimental validation approach. First, we identified a total of 296 CPT targets, 239 of which were also HCC-related targets. We elucidated the mechanisms by which CPT affects HCC through multiple network analysis, including CPT-target network analysis, protein-protein interaction network analysis, target-function network analysis, and pathway enrichment analysis. In addition, we found that CPT induced apoptosis in Huh7 and MHCC97-H ells due to increased levels of cleaved PARP, Bax, and cleaved caspase-3 and decreased Bcl-2 expression. CPT also induced autophagy in HCC cells by increasing LC3-II conversion and the expression of Beclin1 and ATG5, while decreasing the expression of p62/SQSTM1. Autophagy inhibitors (3-methyladenine and chloroquine) enhanced CPT-induced proliferation and apoptosis, suggesting that CPT-induced autophagy may protect HCC cells against cell death. Furthermore, CPT was found to inhibit the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway. Interestingly, activation of PI3K by insulin-like growth factor-I inhibited CPT-induced apoptosis and autophagy, suggesting that the PI3K/AKT/mTOR signaling pathway is involved in both CPT-induced apoptosis and autophagy. Finally, CPT was found to inhibit the growth of Huh7 xenograft tumors. In conclusion, we first demonstrated the antitumor effects of CPT in Huh7 and MHCC97-H cells, both in vitro and in vivo. We elucidated the potential antitumor mechanism of CPT, which involved inducing apoptosis and autophagy by inhibiting the PI3K/Akt/mTOR signaling pathway. Our findings may provide valuable insights into the clinical application of CPT, serving as a potential candidate therapeutic agent for HCC treatment.

Dataset Information

Novel therapeutic features of disulfiram against hepatocellular carcinoma cells with inhibitory effects on a disintegrin and metalloproteinase 10.

Publications

Novel therapeutic features of disulfiram against hepatocellular carcinoma cells with inhibitory effects on a disintegrin and metalloproteinase 10.

Similar Datasets

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