Exogenous hydrogen sulfide promotes C6 glioma cell growth through activation of the p38 MAPK/ERK1/2-COX-2 pathways

Abstract

Abstract. Hydrogen sulfide (H 2 S) participates in multifarious physiological and pathophysiologic progresses of cancer both in vitro and in vivo.We have previously demonstrated that exogenous H 2 S promoted liver cancer cells proliferation/anti-apoptosis/angiogenesis/migration effects via amplifying the activation of NF-κB pathway. However, the effects of H 2 S on cancer cell proliferation and apoptosis are controversial and remain unclear in C6 glioma cells. The present study investigated the effects of exogenous H 2 S on cancer cells growth via activating p38 MAPK/ERK1/2-COX-2 pathways in C6 glioma cells. C6 glioma cells were treated with 400 µmol/l NaHS (a donor of H 2 S) for 24 h. The expression levels of phosphorylated (p)-p38 MAPK, total (t)-p38 MAPK, p-ERK1/2, t-ERK1/2, cyclooxygenase-2 (COX-2) and caspase-3 were measured by western blotting assay. Cell viability was detected by Cell Counting . Apoptotic cells were observed by Hoechst 33258 staining assay. Cell proliferation was directly detected under fully automatic inverted microscope. Exposure of C6 glioma cells to NaHS resulted in cell proliferation, as evidenced by an increase in cell viability. In addition, NaHS treatment reduced apoptosis, as indicated by the decreased apoptotic percentage and the cleaved caspase-3 expression. Importantly, exposure of the cells to NaHS increased the expression levels of p-p38 MAPK, p-ERK1/2 and COX-2. Notably, co-treatment of C6 glioma cells with 400 µmol/l NaHS and AOAA (an inhibitor of CBS) largely suppressed the above NaHS-induced effects. Combined treatment with NaHS and SB203580 (an inhibitor of p38 MAPK) or PD-98059 (an inhibitor of ERK1/2) resulted in the synergistic reduction of COX-2 expression and increase of caspase-3 expression, a decreased number of apoptotic cells, along with decreased cell viability. Combined treatment with NS-398 (an inhibitor of COX-2) and NaHS also resulted in the synergistic increase of caspase-3, a decreased in the number of apoptotic cells and the decrease in cell viability. The findings of the present study provide novel evidence that p38 MAPK/ERK1/2-COX-2 pathways are involved in NaHS-induced cancer cell proliferation and anti-apoptosis in C6 glioma cells.

Cystathionine-β-Synthase Inhibition for Colon Cancer: Enhancement of the Efficacy of Aminooxyacetic Acid via the Prodrug Approach

“…Several lines of studies show that exogenously administered or endogenously produced H 2 S can induce pro-proliferative signaling pathways (including MAP kinases, Akt, ERK1 activation) (5)(6)(7)(35)(36)(37)(38)(39)(40)(41)(42)(43). By inhibiting colon cancer cell H 2 S production, YD0171 may suppress these signaling processes, although this remains to be directly investigated in future studies.…”

Exogenous hydrogen sulfide exerts proliferation, anti-apoptosis, angiopoiesis and migration effects via activating HSP90 pathway in EC109 cells

“…H 2 S enhances the supply of nutrients and blood to the tumor cells and tissues (29). Our latest research also showed that exogenous H 2 S promoted cancer cell proliferation/antiapoptosis/angiogenesis/migration effects via amplifying the activation of NF-κB (30) and p38 MAPK/ERK1/2-COX-2 pathways (31). However, research focused on the effect of exogenous H 2 S on esophageal EC109 cells and its potential mechanisms is lacking.…”

Exogenous hydrogen sulfide promotes hepatocellular carcinoma cell growth by activating the STAT3-COX-2 signaling pathway

“…This indicates that exogenous H 2 S can activate the STAT3 and COX-2 signaling pathways in PLC/PRF/5 cells. Previous studies have shown that the STAT3 (13-17) and COX-2 (32,(43)(44)(45) signaling pathways are associated with tumorigenesis. The present study hypothesized that the STAT3 and COX-2 signaling pathways may be involved in the effects of exogenous H 2 S on the growth of PLC/PRF/5 cells.…”

“…H 2 S can protect cancer cells from chemopreventive agent β-phenylethyl isothiocyanate-induced apoptosis (30) and promote proliferation (30), which may be mediated by the increase in Akt and extracellular signal-regulated kinase (ERK) phosphorylation, and the decrease in p21 Waf1/Cip1 expression and NO production. A recent study by our group revealed that exogenous H 2 S promotes C6 glioma cell growth through the activation of the p38 MAPK/ERK1/2-COX-2 signaling pathway (32). Furthermore, in PLC/PRF/5 cells, exogenous H 2 S exerts proliferation, anti-apoptosis, angiogenesis and migration effects via amplifying the activation of the nuclear factor (NF)-κB signaling pathway (24).…”

“…However, the potential mechanism of H 2 S in cancer is unclear and controversial. Accumulating evidences have demonstrated that H 2 S promotes cancer progression, including proliferation, migration and invasion (28)(29)(30)(31)(32)(33)(34). H 2 S can protect cancer cells from chemopreventive agent β-phenylethyl isothiocyanate-induced apoptosis (30) and promote proliferation (30), which may be mediated by the increase in Akt and extracellular signal-regulated kinase (ERK) phosphorylation, and the decrease in p21 Waf1/Cip1 expression and NO production.…”