Metabolic Reprogramming of Sulfur in Hepatocellular Carcinoma and Sulfane Sulfur-Triggered Anti-Cancer Strategy.

Shi Xu,Ximing Zhang,Yingying Wang,Xiang Ni,Hui Zhang,Mianrong Chen,Xue Zheng,Chun-tao Yang

doi:10.3389/fphar.2020.571143

Abstract

Metabolic reprogramming is a cancer hallmark. Although the reprogramming of central carbon has been well documented, the role of sulfur metabolism has been largely overlooked. Additionally, the effects of sulfur are sometimes contradictory in tumorigenesis. In this study, we aimed to investigate the gene expression profile in hepatocellular carcinoma (HCC) and the effects of reactive sulfur species (RSS) on HCC tumor cells. Furthermore, the cell imaging technology was applied to discover some potential anti-cancer compounds. Gene Set Enrichment Analysis (GSEA) of Gene Expression Omnibus (GEO) dataset (GSE102083) revealed that sulfur amino acid-related metabolism and vitamin B6 binding activity in HCC tissues were downregulated. Calculation of the interaction network identified nine hub genes, among which eight were validated by differential expression and survival analysis in the TCGA_LIHC cohort, and two (CSE and CBS) had the highest enrichment degree. The metabolomics analysis suggested that the hub genes were associated with RSS metabolism including H2S, H2S2, cystine, cysteine, homocysteine, cystathionine, and methionine. The cell viability assay demonstrated that H2S2 had significant anti-cancer effects in HCC SNU398 tumor cells. The cell imaging assay showed that treatment with H2S2 remarkably increased intracellular sulfane sulfur content. On this basis, the anti-cancer activity of some other sulfane sulfur compounds, such as DATS and DADS, was further verified. Lastly, according to the fact that HCC tumor cells preferentially take in cystine due to high expression of SLC7A11 (a cystine/glutamate transporter), persulfided cysteine precursor (PSCP) was tested for its sulfane sulfur release capability and found to selectively inhibit HCC tumor cell viability. Collectively, this study uncovered sulfur metabolism in HCC was reprogrammed, and provided a potential therapeutic strategy for HCC by donating sulfane sulfur.

Highlights

In liver cancer, hepatocellular carcinoma (HCC) is the most common primary malignancy, which has been the leading cause of cancer-related death globally
We observed the sulfur metabolism was reprogrammed in HCC through the bioinformatic Gene Set Enrichment Analysis (GSEA) screening
The scanning revealed that the gene sets of sulfur amino acid metabolism, cysteine and methionine metabolism, and vitamin B6 binding activity were remarkably impaired in HCC tissues

Summary

Introduction

Hepatocellular carcinoma (HCC) is the most common primary malignancy, which has been the leading cause of cancer-related death globally. Many HCC patients may not have the chance of surgical resection because the diagnosis usually occurs at the late stage. Studies supported that many of garlic’s effects are attributed to the generation of sulfane sulfur, a reactive sulfur species (RSS) (Iciek et al, 2001; Iciek et al, 2012). The effects of these RSS on cancer therapy including HCC are contradictory, as both anti-cancer (Iciek et al, 2001; Iciek et al, 2012) and pro-cancer (Pan et al, 2014; Zhen et al, 2018; Yang et al, 2019b) activities have been reported, which hinders the sulfurbased HCC therapy

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