Hydrogen sulfide acts as a double-edged sword in human hepatocellular carcinoma cells through EGFR/ERK/MMP-2 and PTEN/AKT signaling pathways

Dongdong Wu,Wenke Tian,Huijuan Wang,Yanzhang Li,Mengling Li,Shuaiwei Wang,Longzhen Cui,Hui Li,Ailing Ji

doi:10.1038/s41598-017-05457-z

Dongdong Wu, Wenke Tian + Show 7 more

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https://doi.org/10.1038/s41598-017-05457-z

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Journal: Scientific Reports	Publication Date: Jul 11, 2017
Citations: 88	License type: open-access

Affiliation: Henan University

Abstract

Hydrogen sulfide (H2S) is involved in cancer biological processes. However, there are several controversies concerning the role of H2S in cancer development and progression. In this study, we found that the growth and migration of hepatocellular carcinoma (HCC) cells were enhanced by 10–100 μM NaHS and dose-dependently inhibited by 600–1000 μM NaHS. The apoptotic levels were reduced by 25–100 μM NaHS but increased by 400–1000 μM NaHS in HCC cells. After treatment with 25–50 μM NaHS, the protein levels of p-EGFR, p-ERK, MMP-2, and p-AKT were increased, whereas the levels of PTEN and the ratio of BAX/BCL-2 were down-regulated. Administration of 800–1000 μM NaHS showed opposite effects on these protein levels in HCC cells. However, H2S showed no effects on the growth, migration, apoptosis, and the protein levels of the EGFR/ERK/MMP-2 and PTEN/AKT signaling pathways in L02 cells. Furthermore, 25–100 μM NaHS promoted HCC tumor growth and blood vessel formation, while 800–1000 μM NaHS inhibited angiogenesis and tumor growth with no obvious systemic toxicity. These results indicate that H2S acts as a double-edged sword in HCC cells through EGFR/ERK/MMP-2 and PTEN/AKT signaling pathways. Novel H2S donors could be designed and applied for further antitumor research.

Highlights

The enzymes for endogenous H2S production, cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS), and 3-mercaptopyruvate sulfotransferase (3-MST), have been found in many cancers, including colon, liver, ovarian, breast, gastric, and prostate cancers[14]
The levels of H2S in SMMC-7721 and Huh-7cells, as well as in the supernatant were notably higher than those in L02 cells and the supernatant (Fig. 1E and F). These results indicated that H2S could be involved in the development and progression of human hepatocellular carcinoma (HCC) cells
These results suggested that H2S plays an important role in the regulation of liver cancer cell growth and migration

Summary

Introduction

The enzymes for endogenous H2S production, cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS), and 3-mercaptopyruvate sulfotransferase (3-MST), have been found in many cancers, including colon, liver, ovarian, breast, gastric, and prostate cancers[14]. Several studies have shown that H2S endogenously stimulates angiogenesis and promotes tumor cell growth and proliferation[2, 14, 15]. Blocking H2S production resulted in suppression of hepatocellular carcinoma (HCC) growth by suppressing cell growth-related signaling and stimulating mitochondrial apoptosis[16]. Treatment of human hepatoma HepG2 cells and colorectal carcinoma HCT116 cells with 400 μM GYY4137 (a slow-releasing H2S donor) showed anticancer activity partly by promoting apoptosis[17]. H2S could promote HCC cell growth, whereas high concentrations of H2S might exhibit anticancer effects. To test this hypothesis, we determined the effects of different concentrations of NaHS (an H2S donor) on the growth of human HCC cells in vitro and in vivo and clarified the associated molecular mechanisms

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