Center 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.
Int J Oncol. 2014 Apr;44(4):1259-67. doi: 10.3892/ijo.2014.2305. Epub 2014 Feb 14.
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.
GYY4137 是一种硫化氢（H2S）供体，通过细胞周期停滞和促进细胞凋亡的联合作用表现出抗癌活性，并抑制肿瘤生长，但涉及的确切机制尚不清楚。在本研究中，我们发现 GYY4137 介导的人肝癌（HCC）细胞系中细胞增殖的抑制和皮下 HepG2 异种移植模型中肿瘤生长的抑制可能是由于直接靶向信号转导和转录激活因子 3（STAT3）途径。我们发现 GYY4137 通过有效降低 HepG2 和 Bel7402 细胞中 p-STAT3（Y705）水平来抑制 STAT3 激活。STAT3 调节的下游蛋白表达水平的改变，包括 Bcl-2、细胞周期蛋白 D1、Mcl-1、存活素、血管内皮生长因子（VEGF）和缺氧诱导因子-1α（HIF-1α），可能有助于 G1/S 细胞周期转换和血管生成的抑制。在 HepG2 和 Bel7402 细胞中，增加的裂解半胱天冬酶-9、半胱天冬酶-3 和多聚（ADP-核糖）聚合酶（PARP）裂解可能诱导细胞凋亡。在体内，GYY4137 通过抑制 STAT3 激活及其靶基因表达，显著抑制皮下 HepG2 异种移植模型中的肿瘤生长。这些结果表明，GYY4137 介导的 HCC 生长抑制可能是由于抑制了 STAT3 途径。
