S-adenosylmethionine, a methyl donor, up regulates tissue inhibitor of metalloproteinase-2 in colorectal cancer

Hussain, Zahid; Khan, Mohammad Imran; Shahid, Mohammad; Almajhdi, Fahad N.

doi:10.4238/2013.april.10.6

Cited by 22 publications

(19 citation statements)

References 35 publications

(53 reference statements)

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“…The current concentrations of SAM where the inhibition of proliferation of HCT116 cells was noted (1–3 mM), in fact, are comparable with the concentration range of SAM used in prior studies: the antiproliferative effects were typically reported at 1–10 mM [54,56]. When designing the experiments shown in the current report, one of the questions we wished to determine was whether that the antiproliferative effects of SAM are related to an ‘over-stimulation’ of CBS, followed by an elevation of intracellular H 2 S to cytotoxic levels.…”

Section: Discussionsupporting

confidence: 59%

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Effect of S-adenosyl-l-methionine (SAM), an allosteric activator of cystathionine-β-synthase (CBS) on colorectal cancer cell proliferation and bioenergetics in vitro

et al. 2014

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Recent data show that colon cancer cells selectively overexpress cystathionine-β-synthase (CBS), which produces hydrogen sulfide (H2S), 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 H2S 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 H2S production. SAM exerted time-and concentration-dependent modulatory effects on cell proliferation. At 0.1–1 mM SAM increased HCT116 proliferation between 0–12 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 (1h) 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 (72h) 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 H2S production in HCT116 cells is stimulated by the allosteric CBS activator, SAM. At low-to intermediate levels and early time periods the resulting H2S 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 H2S resulting from CBS over-stimulation but, rather to CBS-independent pharmacological effects.

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Section: Discussionsupporting

confidence: 59%

“…SAM has been previously implicated as a negative regulator of tumor cell proliferation by affecting a variety of pathways including DNA methylation and polyamine biosynthesis [52–56]. What relevance, if any, do the current findings have to the anticancer effects of SAM?…”

Section: Discussionmentioning

confidence: 70%

Effect of S-adenosyl-l-methionine (SAM), an allosteric activator of cystathionine-β-synthase (CBS) on colorectal cancer cell proliferation and bioenergetics in vitro

et al. 2014

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“…Poplineau et al [26] reported that a DNA hypomethylation agent enhanced upregulation of MMP-1 gene expression and triggered tumor cell invasion. In contrast, treatment with S-adenosylmethionine, a methyl donor, resulted in activation of TIMP-2 and significant downregulation of MMP-2 and MT1-MMP gene in colorectal cancer [27] . Prognostic values of promoter hypermethylation in patients with gastric cancer documented that patients with higher stage of colorectal cancer possess a higher concentration of methylated APC, TIMP-3 and hMLH1 in the serum [28] .…”

Section: Chromatin Remodeling and Epigenetic Modifications As Etiologmentioning

confidence: 93%

Matrix metalloproteinases and gastrointestinal cancers: Impacts of dietary antioxidants

Verma

Kesh

Ganguly

et al. 2014

WJBC

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teinase (TIMP) which bind MMPs with a 1:1 stoichiometry. In addition, RECK (reversion including cysteinerich protein with kazal motifs) is a membrane bound glycoprotein that inhibits MMP-2, -9 and -14. Moreover, α2-macroglobulin mediates the uptake of several MMPs thereby inhibit their activity. Cancerous conditions increase intrinsic reactive oxygen species (ROS) through mitochondrial dysfunction leading to altered protease/ anti-protease balance. ROS, an index of oxidative stress is also involved in tumorigenesis by activation of different MAP kinase pathways including MMP induction. Oxidative stress is involved in cancer by changing the activity and expression of regulatory proteins especially MMPs. Epidemiological studies have shown that high intake of fruits that rich in antioxidants is associated with a lower cancer incidence. Evidence indicates that some antioxidants inhibit the growth of malignant cells by inducing apoptosis and inhibiting the activity of MMPs. This review is discussed in six subchapters, as follows. AbstractThe process of carcinogenesis is tightly regulated by antioxidant enzymes and matrix degrading enzymes, namely, matrix metalloproteinases (MMPs). Degradation of extracellular matrix (ECM) proteins like collagen, proteoglycan, laminin, elastin and fibronectin is considered to be the prerequisite for tumor invasion and metastasis. MMPs can degrade essentially all of the ECM components and, most MMPs also substantially contribute to angiogenesis, differentiation, proliferation and apoptosis. Hence, MMPs are important regulators of tumor growth both at the primary site and in distant metastases; thus the enzymes are considered as important targets for cancer therapy. The implications of MMPs in cancers are no longer mysterious; however, the mechanism of action is yet to be explained. Herein, our major interest is to clarify how MMPs are tied up with gastrointestinal cancers. Gastrointestinal cancer is a variety of cancer types, including the cancers of gastrointestinal tract and organs, i.e., esophagus, stomach, biliary system, pancreas, small intestine, large intestine, rectum and anus. The activity of MMPs is regulated by its endogenous inhibitor tissue inhibitor of metallopro-

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“…There is extensive in vitro evidence that SAM suppress both growth and invasion in highly invasive cell lines (Pakneshan et al, 2004;Shukeir et al, 2006). In vivo, SAM was demonstrated to inhibit invasiveness and metastasis of human breast (Pakneshan et al, 2004), prostate and colorectal cancer cell lines (Hussain et al, 2013). Several studies demonstrated that SAM treatment had a chemopreventive effect in liver cancer in rat (Pascale et al, 2002).…”

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confidence: 99%

DNA demethylation and invasive cancer: implications for therapeutics

Cheishvili

Boureau

Szyf

2015

British J Pharmacology

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One of the hallmarks of cancer is aberrant DNA methylation, which is associated with abnormal gene expression. Both hypermethylation and silencing of tumour suppressor genes as well as hypomethylation and activation of prometastatic genes are characteristic of cancer cells. As DNA methylation is reversible, DNA methylation inhibitors were tested as anticancer drugs with the idea that such agents would demethylate and reactivate tumour suppressor genes. Two cytosine analogues, 5-azacytidine (Vidaza) and 5-aza-2′-deoxycytidine, were approved by the Food and Drug Administration as antitumour agents in 2004 and 2006 respectively. However, these agents might cause activation of a panel of prometastatic genes in addition to activating tumour suppressor genes, which might lead to increased metastasis. This poses the challenge of how to target tumour suppressor genes and block cancer growth with DNA-demethylating drugs while avoiding the activation of prometastatic genes and precluding the morbidity of cancer metastasis. This paper reviews current progress in using DNA methylation inhibitors in cancer therapy and the potential promise and challenges ahead. LINKED ARTICLESThis article is part of a themed section on Epigenetics and Therapy. To view the other articles in this section visit http://dx.doi. org/10.1111/bph.2015.172.issue-11 Abbreviations 5-azaC, 5-azacytidine; 5-azadC, 5-aza-2′-deoxycytidine; FDA, Food and Drug Administration; HDAC, histone deacetylase; SAH, S-adenosyl-homocysteine; SAHA, suberoylanilide hydroxamic acid; SAM, S-adenosyl-methionine Tables of Links DNA methylation overviewDNA methylation is an enzymatically catalysed covalent modification of DNA, occurring typically in the context of cytosine-phosphate-guanine (CpG) dinucleotides. In general, regions with high CpG content, named CpG islands, are demethylated in normal cells, whereas regions with an intermediate or low density of CpGs are differentially methylated in some tissues, but not in others (Bird et al., 1985). Although rarely observed, non-CpG methylation is mainly found in embryonic stem cells (Lister et al., 2009), but its function needs to be further explored. However, non-CpG methylation is abundant in adult brains, and recent data suggest that it plays a role in silencing promoter activity similar to CpG methylation (Guo et al., 2013;Lister et al., 2013). DNA methyltransferases (DNMTs) catalyse the transfer of a methyl group from its donor S-adenosine-methionine (SAM) to the cytosine nucleotide of DNA. Three distinct phylogenic DNMTs were identified in mammals. DNMT1 is a maintenance DNMT, which shows preference for hemimethylated DNA in vitro and faithfully copies DNA methylation in a cytosine-guanine (CG) palindromic dinucleotide from the parental strand to the daughter strand during cell division (Zucker et al., 1985;Flynn et al., 1996;Pradhan et al., 1999;Fatemi et al., 2001). DNMT3a and DNMT3b methylate unmethylated and hemimethylated DNA at an equal rate, which is consistent with a de novo methylation function (Okano et ...

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S-adenosylmethionine, a methyl donor, up regulates tissue inhibitor of metalloproteinase-2 in colorectal cancer

Cited by 22 publications

References 35 publications

Effect of S-adenosyl-l-methionine (SAM), an allosteric activator of cystathionine-β-synthase (CBS) on colorectal cancer cell proliferation and bioenergetics in vitro

Effect of S-adenosyl-l-methionine (SAM), an allosteric activator of cystathionine-β-synthase (CBS) on colorectal cancer cell proliferation and bioenergetics in vitro

Matrix metalloproteinases and gastrointestinal cancers: Impacts of dietary antioxidants

DNA demethylation and invasive cancer: implications for therapeutics

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