GYY4137, a hydrogen sulfide (H2S) donor, shows potent anti-hepatocellular carcinoma activity through blocking the STAT3 pathway

Lu,Sen; Gao,Yun; Huang,Xinli; Wang,Xuehao

doi:10.3892/ijo.2014.2305

GYY4137, a hydrogen sulfide (H2S) donor, shows potent anti-hepatocellular carcinoma activity through blocking the STAT3 pathway

Authors:
- Sen Lu
- Yun Gao
- Xinli Huang
- Xuehao Wang
View Affiliations

Affiliations: 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
Published online on: February 14, 2014 https://doi.org/10.3892/ijo.2014.2305
Pages: 1259-1267

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

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.

View Figures

View References

1.	Bruix J and Sherman M; Practice Guidelines Committee; American Association for the Study of Liver Diseases: Management of hepatocellular carcinoma. Hepatology. 42:1208–1236. 2005. View Article : Google Scholar
2.	Villanueva A, Newell P, Chiang DY, Friedman SL and Llovet JM: Genomics and signaling pathways in hepatocellular carcinoma. Semin Liver Dis. 27:55–76. 2007. View Article : Google Scholar : PubMed/NCBI
3.	Llovet JM and Bruix J: Novel advancements in the management of hepatocellular carcinoma in 2008. J Hepatol. 48(Suppl 1): S20–S37. 2008. View Article : Google Scholar : PubMed/NCBI
4.	Niu G, Wright KL, Huang M, et al: Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene. 21:2000–2008. 2002. View Article : Google Scholar : PubMed/NCBI
5.	Real PJ, Sierra A, De Juan A, Segovia JC, Lopez-Vega JM and Fernandez-Luna JL: Resistance to chemotherapy via Stat3-dependent overexpression of Bcl-2 in metastatic breast cancer cells. Oncogene. 21:7611–7618. 2002. View Article : Google Scholar
6.	Wang T, Niu G, Kortylewski M, et al: Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med. 10:48–54. 2004. View Article : Google Scholar : PubMed/NCBI
7.	Schindler C, Levy DE and Decker T: JAK-STAT signaling: from interferons to cytokines. J Biol Chem. 282:20059–20063. 2007. View Article : Google Scholar : PubMed/NCBI
8.	Alvarez JV, Febbo PG, Ramaswamy S, Loda M, Richardson A and Frank DA: Identification of a genetic signature of activated signal transducer and activator of transcription 3 in human tumors. Cancer Res. 65:5054–5062. 2005. View Article : Google Scholar : PubMed/NCBI
9.	Bollrath J, Phesse TJ, von Burstin VA, et al: gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis. Cancer Cell. 15:91–102. 2009. View Article : Google Scholar : PubMed/NCBI
10.	Garcia R, Bowman TL, Niu G, et al: Constitutive activation of Stat3 by the Src and JAK tyrosine kinases participates in growth regulation of human breast carcinoma cells. Oncogene. 20:2499–2513. 2001. View Article : Google Scholar
11.	Liu Y, Liu A, Li H, Li C and Lin J: Celecoxib inhibits interleukin-6/interleukin-6 receptor-induced JAK2/STAT3 phosphorylation in human hepatocellular carcinoma cells. Cancer Prev Res (Phila). 4:1296–1305. 2011. View Article : Google Scholar : PubMed/NCBI
12.	Yang J, Cai X, Lu W, et al: Evodiamine inhibits STAT3 signaling by inducing phosphatase shatterproof 1 in hepatocellular carcinoma cells. Cancer Lett. 328:243–251. 2013. View Article : Google Scholar : PubMed/NCBI
13.	Gu FM, Li QL, Gao Q, et al: Sorafenib inhibits growth and metastasis of hepatocellular carcinoma by blocking STAT3. World J Gastroenterol. 17:3922–3932. 2011. View Article : Google Scholar : PubMed/NCBI
14.	Rajendran P, Ong TH, Chen L, et al: Suppression of signal transducer and activator of transcription 3 activation by butein inhibits growth of human hepatocellular carcinoma in vivo. Clin Cancer Res. 17:1425–1439. 2011. View Article : Google Scholar : PubMed/NCBI
15.	Calvisi DF, Ladu S, Gorden A, et al: Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology. 130:1117–1128. 2006. View Article : Google Scholar : PubMed/NCBI
16.	Hu LF, Wong PT, Moore PK and Bian JS: Hydrogen sulfide attenuates lipopolysaccharide-induced inflammation by inhibition of p38 mitogen-activated protein kinase in microglia. J Neurochem. 100:1121–1128. 2007. View Article : Google Scholar : PubMed/NCBI
17.	Rose P, Moore PK, Ming SH, Nam OC, Armstrong JS and Whiteman M: Hydrogen sulfide protects colon cancer cells from chemopreventative agent beta-phenylethyl isothiocyanate induced apoptosis. World J Gastroenterol. 11:3990–3997. 2005.PubMed/NCBI
18.	Lee ZW, Zhou J, Chen CS, et al: The slow-releasing hydrogen sulfide donor, GYY4137, exhibits novel anti-cancer effects in vitro and in vivo. PLoS One. 6:e210772011. View Article : Google Scholar : PubMed/NCBI
19.	Li L, Fox B, Keeble J, et al: The complex effects of the slow-releasing hydrogen sulfide donor GYY4137 in a model of acute joint inflammation and in human cartilage cells. J Cell Mol Med. 17:365–376. 2013. View Article : Google Scholar : PubMed/NCBI
20.	Takada Y, Ichikawa H, Badmaev V and Aggarwal BB: Acetyl-11-keto-beta-boswellic acid potentiates apoptosis, inhibits invasion, and abolishes osteoclastogenesis by suppressing NF-kappa B and NF-kappa B-regulated gene expression. J Immunol. 176:3127–3140. 2006. View Article : Google Scholar
21.	Isomoto H, Mott JL, Kobayashi S, et al: Sustained IL-6/STAT-3 signaling in cholangiocarcinoma cells due to SOCS-3 epigenetic silencing. Gastroenterology. 132:384–396. 2007. View Article : Google Scholar : PubMed/NCBI
22.	Won C, Lee CS, Lee JK, et al: CADPE suppresses cyclin D1 expression in hepatocellular carcinoma by blocking IL-6-induced STAT3 activation. Anticancer Res. 30:481–488. 2010.PubMed/NCBI
23.	Aggarwal BB, Kunnumakkara AB, Harikumar KB, et al: Signal transducer and activator of transcription-3, inflammation, and cancer: how intimate is the relationship? Ann NY Acad Sci. 1171:59–76. 2009. View Article : Google Scholar : PubMed/NCBI
24.	Lufei C, Koh TH, Uchida T and Cao X: Pin1 is required for the Ser727 phosphorylation-dependent Stat3 activity. Oncogene. 26:7656–7664. 2007. View Article : Google Scholar : PubMed/NCBI
25.	Aziz MH, Manoharan HT, Church DR, et al: Protein kinase Cepsilon interacts with signal transducers and activators of transcription 3 (Stat3), phosphorylates Stat3Ser727, and regulates its constitutive activation in prostate cancer. Cancer Res. 67:8828–8838. 2007. View Article : Google Scholar : PubMed/NCBI
26.	Selvendiran K, Kuppusamy ML, Ahmed S, et al: Oxygenation inhibits ovarian tumor growth by downregulating STAT3 and cyclin-D1 expressions. Cancer Biol Ther. 10:386–390. 2010. View Article : Google Scholar : PubMed/NCBI
27.	Ai T, Wang Z, Zhang M, et al: Expression and prognostic relevance of STAT3 and cyclin D1 in non-small cell lung cancer. Int J Biol Markers. 27:e132–e138. 2012. View Article : Google Scholar : PubMed/NCBI
28.	Zhang K, Pang B, Xin T, et al: Increased signal transducer and activator of transcription 3 (STAT3) and decreased cyclin D1 in recurrent astrocytic tumours compared with paired primary astrocytic tumours. J Int Med Res. 39:2103–2109. 2011. View Article : Google Scholar
29.	Sieghart W, Losert D, Strommer S, et al: Mcl-1 overexpression in hepatocellular carcinoma: a potential target for antisense therapy. J Hepatol. 44:151–157. 2006. View Article : Google Scholar : PubMed/NCBI
30.	Bossy-Wetzel E and Green DR: Apoptosis: checkpoint at the mitochondrial frontier. Mutat Res. 434:243–251. 1999. View Article : Google Scholar : PubMed/NCBI
31.	Estaquier J, Vallette F, Vayssiere JL and Mignotte B: The mitochondrial pathways of apoptosis. Adv Exp Med Biol. 942:157–183. 2012. View Article : Google Scholar
32.	Wurstle ML, Laussmann MA and Rehm M: The central role of initiator caspase-9 in apoptosis signal transduction and the regulation of its activation and activity on the apoptosome. Exp Cell Res. 318:1213–1220. 2012. View Article : Google Scholar : PubMed/NCBI
33.	Wei D, Le X, Zheng L, et al: Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. Oncogene. 22:319–329. 2003. View Article : Google Scholar : PubMed/NCBI
34.	Zhu H, Feng Y, Zhang J, et al: Inhibition of hypoxia inducible factor 1alpha expression suppresses the progression of esophageal squamous cell carcinoma. Cancer Biol Ther. 11:981–987. 2011. View Article : Google Scholar : PubMed/NCBI
35.	Matsuyama T, Nakanishi K, Hayashi T, et al: Expression of hypoxia-inducible factor-1alpha in esophageal squamous cell carcinoma. Cancer Sci. 96:176–182. 2005. View Article : Google Scholar : PubMed/NCBI
36.	Yasuda S, Arii S, Mori A, et al: Hexokinase II and VEGF expression in liver tumors: correlation with hypoxia-inducible factor 1 alpha and its significance. J Hepatol. 40:117–123. 2004. View Article : Google Scholar : PubMed/NCBI
37.	Tanaka H, Yamamoto M, Hashimoto N, et al: Hypoxia-independent overexpression of hypoxia-inducible factor 1alpha as an early change in mouse hepatocarcinogenesis. Cancer Res. 66:11263–11270. 2006. View Article : Google Scholar
38.	Moser C, Lang SA, Mori A, et al: ENMD-1198, a novel tubulin-binding agent reduces HIF-1alpha and STAT3 activity in human hepatocellular carcinoma (HCC) cells, and inhibits growth and vascularization in vivo. BMC Cancer. 8:2062008. View Article : Google Scholar : PubMed/NCBI