Abstract
BackgroundKnowledge about the expression and thus a role of enzymes that produce endogenous H2S - cystathionine-β-synthase, cystathionine γ-lyase and mercaptopyruvate sulfurtransferase - in renal tumors is still controversial. In this study we aimed to determine the expression of these enzymes relatively to the expression in unaffected part of kidney from the same patient and to found relation of these changes to apoptosis. To evaluate patient’s samples, microarray and immunohistochemistry was used.MethodsTo determine the physiological importance, we used RCC4 stable cell line derived from clear cell renal cell carcinoma, where apoptosis induction by a mixture of five chemotherapeutics with/without silencing of H2S-producing enzymes was detected. Immunofluorescence was used to determine each enzyme in the cells.ResultsIn clear cell renal cell carcinomas, expression of H2S-producing enzymes was mostly decreased compared to a part of kidney that was distal from the tumor. To evaluate a potential role of H2S-producing enzymes in the apoptosis induction, we used RCC4 stable cell line. We have found that silencing of cystathionine-β-synthase and cystathionine γ-lyase prevented induction of apoptosis. Immunofluorescence staining clearly showed that these enzymes were upregulated during apoptosis in RCC4 cells.ConclusionBased on these results we concluded that in clear cell renal cell carcinoma, reduced expression of the H2S-producing enzymes, mainly cystathionine γ-lyase, might contribute to a resistance to the induction of apoptosis. Increased production of the endogenous H2S, or donation from the external sources might be of a therapeutic importance in these tumors.
Highlights
Knowledge about the expression and a role of enzymes that produce endogenous Hydrogen sulfide (H2S) cystathionine-β-synthase, cystathionine γ-lyase and mercaptopyruvate sulfurtransferase - in renal tumors is still controversial
We investigated the possible participation of these enzymes on the apoptosis induction in RCC4 stable cell line derived from clear cell renal cell carcinoma (ccRCC)
cystathionine γ-lyase (CSE) expression was downregulated in all patients with renal tumors and not changed in 3 patients with ccRCC and one patient with angiomyolipoma (Fig. 1b)
Summary
Knowledge about the expression and a role of enzymes that produce endogenous H2S cystathionine-β-synthase, cystathionine γ-lyase and mercaptopyruvate sulfurtransferase - in renal tumors is still controversial. The expression level of CBS mRNA is low in hepatocellular carcinoma [8] or gastric and colorectal cancers [9]. Varying expression levels of CBS/CSE were found in human prostate stromal and epithelial compartments [10]. In another study, reduced expression of H2S-producing enzymes was observed in human prostate cancer tissues and in prostate cancer cells [11]. Expression of the CSE, but not CBS was significantly reduced in prostate cancer tissue versus tissue from normal prostate [12]. Sekiguchi et al [13] reported that endogenous H2S produced by CSE may contribute to the proliferation of gastric cancer AGS cells, most probably through anti-apoptotic actions
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