Tumor-derived hydrogen sulfide, produced by cystathionine-β-synthase, stimulates bioenergetics, cell proliferation, and angiogenesis in colon cancer (original) (raw)
Related papers
The Therapeutic Potential of Cystathionine β-Synthetase/Hydrogen Sulfide Inhibition in Cancer
Antioxidants & Redox Signaling, 2015
Significance: Cancer represents a major socioeconomic problem; there is a significant need for novel therapeutic approaches targeting tumor-specific pathways. Recent Advances: In colorectal and ovarian cancers, an increase in the intratumor production of hydrogen sulfide (H 2 S) from cystathionine b-synthase (CBS) plays an important role in promoting the cellular bioenergetics, proliferation, and migration of cancer cells. It also stimulates peritumor angiogenesis inhibition or genetic silencing of CBS exerts antitumor effects both in vitro and in vivo, and potentiates the antitumor efficacy of anticancer therapeutics. Critical Issues: Recently published studies are reviewed, implicating CBS overexpression and H 2 S overproduction in tumor cells as a tumorgrowth promoting ''bioenergetic fuel'' and ''survival factor,'' followed by an overview of the experimental evidence demonstrating the anticancer effect of CBS inhibition. Next, the current state of the art of pharmacological CBS inhibitors is reviewed, with special reference to the complex pharmacological actions of aminooxyacetic acid. Finally, new experimental evidence is presented to reconcile a controversy in the literature regarding the effects of H 2 S donor on cancer cell proliferation and survival. Future Directions: From a basic science standpoint, future directions in the field include the delineation of the molecular mechanism of CBS upregulation of cancer cells and the delineation of the interactions of H 2 S with other intracellular pathways of cancer cell metabolism and proliferation. From the translational science standpoint, future directions include the translation of the recently emerging roles of H 2 S in cancer into human diagnostic and therapeutic approaches. Antioxid. Redox Signal. 22, 424-448. Biological Effects of H 2 S with Relevance for Cancer Biology H 2 S, as a vasodilator and pro-angiogenic mediator Vasorelaxation is one of the first recognized biological effects of H 2 S. Often compared with NO, H 2 S exerts a concentration-dependent vasodilatory effect in blood vessels. The mechanisms of H 2 S-mediated vasodilation include the activation of K ATP channels, a variety of other channels, inhibition of phosphodiesterases, and a synergy with NO (132).
Scientific Reports, 2016
Therapeutic manipulation of the gasotransmitter hydrogen sulfide (H 2 S) has recently been proposed as a novel targeted anticancer approach. Here we show that human lung adenocarcinoma tissue expresses high levels of hydrogen sulfide (H 2 S) producing enzymes, namely, cystathionine beta-synthase (CBS), cystathionine gamma lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST), in comparison to adjacent lung tissue. In cultured lung adenocarcinoma but not in normal lung epithelial cells elevated H 2 S stimulates mitochondrial DNA repair through sulfhydration of EXOG, which, in turn, promotes mitochondrial DNA repair complex assembly, thereby enhancing mitochondrial DNA repair capacity. In addition, inhibition of H 2 S-producing enzymes suppresses critical bioenergetics parameters in lung adenocarcinoma cells. Together, inhibition of H 2 S-producing enzymes sensitize lung adenocarcinoma cells to chemotherapeutic agents via induction of mitochondrial dysfunction as shown in in vitro and in vivo models, suggesting a novel mechanism to overcome tumor chemoresistance. H 2 S is produced in mammalian cells by three distinct enzymes, cystathionine beta-synthase (CBS), cystathionine gamma lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST); during methionine/transsulfuration pathway 1-3. Deregulation of either H 2 S production and/or its downstream actions have been implicated in the pathophysiology of several diseases, including cardiovascular disease, shock, inflammation, diabetes, metabolic syndromes and neurodegeneration 4-11. In connection with cancer, we have previously showed a marked increase in the expression of CBS in colorectal cancer cells (compared to the surrounding normal mucosal margin), which was also recapitulated in multiple colon cancer cell lines 12. ShRNA-mediated silencing, as well as pharmacological inhibition of CBS caused a significant inhibition of the proliferation of colon cancer cells in vitro and in vivo (in tumor-bearing nude mice). Also, silencing or inhibition of CBS suppressed cellular bioenergetics of the colon cancer cells 12. The importance of the CBS/H 2 S in the promotion of cell proliferation and cellular bioenergetics has subsequently been confirmed in ovarian cancer 13 and breast cancer 14. H 2 S generated by overexpressed CSE, has been implicated in melanoma 15. In addition a rapidly increasing body of literature implicates the endogenously generated H 2 S to vascular relaxation and angiogenesis, cell proliferation, mitochondrial function, and cell
Indian Journal of Pharmaceutical Sciences, 2019
Kumarasamy et al.: Role of Hydrogen Sulphide in Colon Cancer Cells Several studies reported the carcinogenic and anticarcinogenic effects of hydrogen sulphide. The present study evaluated the role of mitochondria in mediating the anti/pro-carcinogenic effect of hydrogen sulphide on colon cancer cells as mitochondrial K ATP channel and mitochondrial electron transport chain are one of the promising targets for cancer treatment. The colon adenoma cell line and normal small intestinal epithelial cell lines were used to study the antiproliferative effect of hydrogen sulphide in the presence of enzyme inhibitors, mitochondrial K ATP channel modulators and in presence of inhibitors of endogenous hydrogen sulphide metabolizing enzymes namely cystathionine-β-synthase and cystathionine-γ-lyase. Antiproliferative effect of hydrogen sulphide was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, crystal violet, sulforhodamine B and lactate dehydrogenase assays with its donor sodium hydrogen sulphide in both HT-29 and IEC-6 cells, where only IEC-6 cells showed signifi cant cytotoxic effect at a concentration of 49.88 μg (IC 50) but HT-29 failed to exhibit cytotoxicity with the same hydrogen sulphide concentration. In order to identify the mitochondrial role, several electron transporting chain inhibitors and K ATP channel modulators were used, but still hydrogen sulphide could able to enhance the colon adenoma cell line growth indicating mitochondrial in-dependency in the pro-carcinogenic effect. However, anticarcinogenic effect of hydrogen sulphide was observed only when the cells were incubated in the presence of cystathionine-βsynthase and cystathionine-γ-lyase inhibitor, indicating their infl uential role in determining the exogenous hydrogen sulphide toxicity in colon adenoma cell line cells.
Antioxidants
Cystathionine β-synthase (CBS), CSE (cystathionine γ-lyase) and 3-mercaptopyruvate sulfurtransferase (3-MST) have emerged as three significant sources of hydrogen sulfide (H2S) in various forms of mammalian cancer. Here, we investigated the functional role of CBS’ and 3-MST’s catalytic activity in the murine breast cancer cell line EO771. The CBS/CSE inhibitor aminooxyacetic acid (AOAA) and the 3-MST inhibitor 2-[(4-hydroxy-6-methylpyrimidin-2-yl)sulfanyl]-1-(naphthalen-1-yl)ethan-1-one (HMPSNE) were used to assess the role of endogenous H2S in the modulation of breast cancer cell proliferation, migration, bioenergetics and viability in vitro. Methods included measurements of cell viability (MTT and LDH assays), cell proliferation and in vitro wound healing (IncuCyte) and cellular bioenergetics (Seahorse extracellular flux analysis). CBS and 3-MST, as well as expression were detected by Western blotting; H2S production was measured by the fluorescent dye AzMC. The results show that ...
Molecular Functions of Hydrogen Sulfide in Cancer
Pathophysiology, 2021
Hydrogen sulfide (H2S) is a gasotransmitter that exerts a multitude of functions in both physiologic and pathophysiologic processes. H2S-synthesizing enzymes are increased in a variety of human malignancies, including colon, prostate, breast, renal, urothelial, ovarian, oral squamous cell, and thyroid cancers. In cancer, H2S promotes tumor growth, cellular and mitochondrial bioenergetics, migration, invasion, angiogenesis, tumor blood flow, metastasis, epithelia–mesenchymal transition, DNA repair, protein sulfhydration, and chemotherapy resistance Additionally, in some malignancies, increased H2S-synthesizing enzyme expression correlates with a worse prognosis and a higher tumor stage. Here we review the role of H2S in cancer, with an emphasis on the molecular mechanisms by which H2S promotes cancer development, progression, dedifferentiation, and metastasis.
2016
Long noncoding RNAs (lncRNAs) are emerging as main nodes of regulatory networks underlying developmental processes in Eukaryotes. Their action is particularly relevant in the central nervous system, whose wide variety of cells are highly transcriptionally active and express almost half of the lncRNAs detected in the human brain [1]. In addition, their potential activity as oncosuppressors or oncogenes and their association with cancer subtypes and clinical prognosis is also emerging [2].
Nitric Oxide, 2014
Recent data show that colon cancer cells selectively overexpress cystathionine-b-synthase (CBS), which produces hydrogen sulfide (H 2 S), to maintain cellular bioenergetics, support tumor growth and stimulate angiogenesis and vasorelaxation in the tumor microenvironment. The purpose of the current study was to investigate the effect of the allosteric CBS activator S-adenosyl-L-methionine (SAM) on the proliferation and bioenergetics of the CBS-expressing colon cancer cell line HCT116. The non-transformed, non-tumorigenic colon epithelial cell line NCM356 was used as control. For assessment of cell proliferation, the xCELLigence system was used. Bioenergetic function was measured by Extracellular Flux Analysis. Experiments using human recombinant CBS or HCT116 homogenates complemented the cell-based studies. SAM markedly enhanced CBS-mediated H 2 S production in vitro, especially when a combination of cysteine and homocysteine was used as substrates. Addition of SAM (0.1-3 mM) to HCT116 cells induced a concentration-dependent increase H 2 S production. SAM exerted time-and concentration-dependent modulatory effects on cell proliferation. At 0.1-1 mM SAM increased HCT116 proliferation between 0 and 12 h, while the highest SAM concentration (3 mM) inhibited proliferation. Over a longer time period (12-24 h), only the lowest concentration of SAM used (0.1 mM) stimulated cell proliferation; higher SAM concentrations produced a concentration-dependent inhibition. The short-term stimulatory effects of SAM were attenuated by the CBS inhibitor aminooxyacetic acid (AOAA) or by stable silencing of CBS. In contrast, the inhibitory effects of SAM on cell proliferation was unaffected by CBS inhibition or CBS silencing. In contrast to HCT116 cells, the lower rate of proliferation of the low-CBS expressor NCM356 cells was unaffected by SAM. Short-term (1 h) exposure of HCT116 cells to SAM induced a concentration-dependent increase in oxygen consumption and bioenergetic function at 0.1-1 mM, while 3 mM was inhibitory. Longer-term (72 h) exposure of HCT116 cells to all concentrations of SAM tested suppressed mitochondrial oxygen consumption rate, cellular ATP content and cell viability. The stimulatory effect of SAM on bioenergetics was attenuated in cells with stable CBS silencing, while the inhibitory effects were unaffected. In NCM356 cells SAM exerted smaller effects on cellular bioenergetics than in HCT116 cells. We have also observed a downregulation of CBS in response to prolonged exposure of SAM both in HCT116 and NCM356 cells. Taken together, the results demonstrate that H 2 S production in HCT116 cells is stimulated by the allosteric CBS activator, SAM. At low-to intermediate levels and early time periods the resulting H 2 S serves as an endogenous cancer cell growth and bioenergetic factor. In contrast, the inhibition of cell proliferation and bioenergetic function by SAM does not appear to relate to adverse autocrine effects of H 2 S resulting from CBS over-stimulation but, rather to CBS-independent pharmacological effects.
Nitric Oxide, 2015
Clear cell renal cell carcinoma (ccRCC) is characterized by Von Hippel-Lindau (VHL)-deficiency, resulting in pseudohypoxic, angiogenic and glycolytic tumours. Hydrogen sulfide (H 2 S) is an endogenously-produced gasotransmitter that accumulates under hypoxia and has been shown to be pro-angiogenic and cytoprotective in cancer. It was hypothesized that H 2 S levels are elevated in VHL-deficient ccRCC, contributing to survival, metabolism and angiogenesis. Using the H 2 Sspecific probe MeRhoAz, it was found that H 2 S levels were higher in VHL-deficient ccRCC cell lines compared to cells with wild-type VHL. Inhibition of H 2 S-producing enzymes could reduce the proliferation, metabolism and survival of ccRCC cell lines, as determined by live-cell imaging, XTT/ATP assay, and flow cytometry respectively. Using the chorioallantoic membrane angiogenesis model, it was found that systemic inhibition of endogenous H 2 S production was able to decrease vascularization of VHL-deficient ccRCC xenografts. Endogenous H 2 S production is an attractive new target in ccRCC due to its involvement in multiple aspects of disease.
Cancer Research
The trans-sulfuration enzyme cystathionine-b-synthase (CBS) and its product hydrogen sulfide (H2S) are aberrantly upregulated in colorectal cancers, where they contribute to tumor growth and progression by both autocrine and paracrine mechanisms. However, it is unknown whether the CBS/H2S axis plays a role in colorectal carcinogenesis. Here, we report upregulation of CBS in human biopsies of precancerous adenomatous polyps and show that forced upregulation of CBS in an adenoma-like colonic epithelial cell line is sufficient to induce metabolic and gene expression profiles characteristic of colorectal cancer cells. Differentially expressed metabolites (65 increased and 20 decreased) clustered into the glycolytic pathway, nucleotide sugars, intermediates of the pentose phosphate pathway, and lipogenesis, including primarily phospholipids, sphingolipids, and bile acids. CBS upregulation induced broad changes in the NCM356 cell transcriptome with over 350 differentially expressed genes. These genes overlapped significantly with gene sets related to glycolysis, hypoxia, and a colon cancer cell phenotype, including genes regulated by NF-kB, KRAS, p53, and Wnt signaling, genes downregulated after E-cadherin knockdown, and genes related to increased extracellular matrix, cell adhesion, and epithelial-tomesenchymal transition. The CBS-induced switch to an anabolic metabolism was associated with increased NCM356 cell bioenergetics, proliferation, invasion through Matrigel, resistance to anoikis, and CBS-dependent tumorigenesis in immunocompromised mice. Genetic ablation of CBS in CBS heterozygous mice (CBS þ/À) reduced the number of mutagen-induced aberrant colonic crypt foci. Taken together, these results establish that activation of the CBS/H2S axis promotes colon carcinogenesis.