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GYY4137, a hydrogen sulfide (H₂S) donor, shows potent anti-hepatocellular carcinoma activity through blocking the
Sen Lu1, Yun Gao1, Xinli Huang1
1Center of Liver Transplantation, The First Affiliated Hospital of Nanjing Medical University, The Key Laboratory of Living Donor Liver Transplantation, Ministry of Health, Nanjing 210029, P.R. China.
Abstract:
GYY4137, a hydrogen sulfide (H2S) donor, exhibits anticancer activity by a combination of cell cycle arrest and promoting apoptosis, and inhibits tumor growth, however, the precise mechanisms involved remain unclear. In this study, we discovered that GYY4137-mediated suppression of cell proliferation in human hepatocellular carcinoma (HCC) cell lines and tumor growth in a subcutaneous HepG2 xenograft model may be due to directly targeting the signal transducer and activator of transcription 3 (STAT3) pathway. We found that GYY4137 suppressed STAT3 activation by reducing p-STAT3 (Y705) levels effectively in HepG2 and Bel7402 cells. Altered expression levels of STAT3-regulated downstream proteins including Bcl-2, cyclin D1, Mcl-1, survivin, vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α (HIF-1α) may contribute to the inhibition of G1/S cell cycle transition and angiogenesis. Increased cleaved caspase-9, caspase-3 and poly(ADP-ribose) polymerase (PARP) cleavage may induce cell apoptosis in HepG2 and Bel7402 cells. In vivo, GYY4137 significantly inhibited tumor growth in the subcutaneous HepG2 xenograft model by inhibiting STAT3 activation and its target gene expression. These results suggest that GYY4137-mediated suppression of HCC growth may be due to the inhibition of the STAT3 pathway.
Insights
The hydrogen sulfide donor GYY4137 inhibits hepatocellular carcinoma (HCC) growth by targeting the STAT3 pathway. This compound suppresses cell proliferation, angiogenesis, and promotes apoptosis, offering a potential new therapy for HCC.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Hydrogen sulfide (H2S) donors, like GYY4137, show anticancer potential but their mechanisms in hepatocellular carcinoma (HCC) are not fully understood.
- The signal transducer and activator of transcription 3 (STAT3) pathway is frequently dysregulated in HCC and promotes tumor growth and survival.
Purpose of the Study:
- To investigate the precise mechanisms by which GYY4137 suppresses HCC cell proliferation and tumor growth.
- To determine if GYY4137 directly targets the STAT3 signaling pathway in HCC.
Main Methods:
- Assessing GYY4137's effect on HCC cell lines (HepG2, Bel7402) and a HepG2 xenograft mouse model.
- Analyzing STAT3 activation (p-STAT3 Y705 levels) and downstream target gene expression (Bcl-2, cyclin D1, Mcl-1, survivin, VEGF, HIF-1α).
- Evaluating apoptosis markers (caspase-9, caspase-3, PARP cleavage) and cell cycle progression.
Main Results:
- GYY4137 significantly inhibited STAT3 activation by reducing p-STAT3 (Y705) levels in HCC cell lines.
- GYY4137 altered the expression of STAT3-regulated genes involved in cell cycle (cyclin D1), apoptosis (Bcl-2, Mcl-1, survivin), and angiogenesis (VEGF, HIF-1α).
- GYY4137 induced apoptosis and inhibited tumor growth in vivo by suppressing STAT3 activation and its target gene expression.
Conclusions:
- GYY4137 suppresses HCC cell proliferation and tumor growth, at least partly, by directly inhibiting the STAT3 signaling pathway.
- Targeting the STAT3 pathway with GYY4137 represents a potential therapeutic strategy for hepatocellular carcinoma.
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