Reduced availability of endogenously synthesized methionine for S-adenosylmethionine formation in methionine-dependent cancer cells.

Coalson, Dennis W.; Mecham, James O.; Stern, P; Hoffman, Robert M.

doi:10.1073/pnas.79.14.4248

Cited by 111 publications

(82 citation statements)

References 15 publications

(7 reference statements)

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“…An additional cancer-correlated phenotype that could be associated with this metabolic pathway is the impeded growth that most cancer cells display when methionine is replaced by its immediate metabolic precursor, homocysteine (35,36). This tumor-associated methionine-dependent phenotype has also been observed in vivo and has been used to explain the antitumor mechanism of cis-diammine dichloroplatinum (37).…”

Section: Discussionmentioning

confidence: 99%

Expression Profiling of Homocysteine Junction Enzymes in the NCI60 Panel of Human Cancer Cell Lines

et al. 2005

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Methionine metabolism provides two key cellular reagents: S-adenosylmethionine and glutathione, derived from the common intermediate, homocysteine. A majority of cancer cells exhibit a methionine-dependent phenotype whereby they are unable to grow in medium in which methionine is replaced by its precursor, homocysteine. Additionally, CpG island hypermethylation of tumor suppressor gene promoters is observed in a background of global hypomethylation in cancerous cells. In this study, we have profiled the expression levels of the homocysteine junction enzymes, methionine synthase (MS), MS reductase (MSR), and cystathionine B-synthase (CBS) in the NCI60 panel of cancer cell lines. The doubling time of non-small lung cell cancer lines, which exhibit the lowest levels of MS within the panel, was significantly correlated with expression of MS. The ratio of MS to MSR varied over a 5-fold range in the different cell types, which may modulate methionine synthesis. Interestingly, markedly reduced CBS expression was seen in the methionine-dependent prostate cancer cell line, PC-3, but not in the methionine-independent cell line, DU-145. However, neither provision of the transsulfuration pathway product, cysteine, nor overexpression of CBS rescued the growth impairment, indicating that reduced CBS was not responsible for the methionine-dependent phenotype in this cell line. (Cancer Res 2005; 65(4): 1554-60)

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Section: Discussionmentioning

confidence: 99%

Expression Profiling of Homocysteine Junction Enzymes in the NCI60 Panel of Human Cancer Cell Lines

et al. 2005

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“…It should be noted that CDD-fed rodents have lower methionine levels, as choline is a precursor of methionine (27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38), which may inhibit tumor growth in the liver, due to the enhanced requirement of cancer cells for methionine.…”

Section: Comparison Of Cells From Metastases In Fatty and Normal Livementioning

confidence: 99%

Choline-Deficient-Diet-Induced Fatty Liver Is A Metastasis-Resistant Microenvironment

Nakamura

Suetsugu

Hasegawa

et al. 2017

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Abstract. Background Non-alcoholic fatty liver disease (NAFLD) has increased in developed countries, with a prevalence of 20-30% in Europe and the United States and 12-30% in Asia (1-8). Obesity is a risk factor for NAFLD and has influenced the increase in NAFLD (9). An important question is whether fatty liver has an influence on cancer metastasis.We have previously shown that murine EL4-RFP malignant lymphoma cells metastasize to multiple sites including the liver (10, 11). We have previously described color-coded imaging of the tumor microenvironment (TME) of cancer cells (11)(12)(13)(14)(15)(16)(17)(18)(19)(20).A syngeneic color-coded imageable lymphoma model, using the EL4 cell line, was previously developed to visualize recruitment of host stromal cells in the TME during metastasis. Large EL4-RFP liver metastases in C57BL/6-GFP mice contained GFP-expressing stromal cells derived from the host (10). A subsequent study whereby liver metastases were formed after splenic injection of EL4-RFP cells also demonstrated that the liver metastases were rich in stromal cells including macrophages, fibroblasts, dendritic cells and normal lymphocytes (11).In the present report, the TME of EL4-RFP metastasis in mice with fatty liver and normal liver were compared, with the use of EL4-RFP. Materials and MethodsGFP transgenic mice. Transgenic C57BL/6-GFP mice were obtained from the

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“…Total cellular protein measurement Determinations were done as described by Coalson et al, 1982. AdoMet/AdoHcy measurements thiolactone was synthesized by a mohificatiok of t h i Determinations were done using VYDAC cation-exprocedure of Baernstein (1934 First, the separation of methionine pCi/ml for 24 h at 37°C in 95% air/5% C02. from homocysteine and from other sulfur-containing After labeling for 24 h, the wells were cooled on ice, amino acids and peptides was determined by running the medium was removed, and the wells were washed standards of methionine, homocysteine, S-adenosylhomthree times with 1 ml ice-cold portions of phosphate-ocysteine, cysteine, cystathionine, and reduced glutathibuffered saline (0.15 M NaC1; 10 mM sodium phosphate, one.…”

Section: Radioactive Labels [35s]met Was Purchased Frommentioning

confidence: 99%

Reduced free‐methionine in methionine‐dependent SV40‐transformed human fibroblasts synthesizing apparently normal amounts of methionine

Stern

Mecham

Wallace

et al. 1983

Journal Cellular Physiology

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Many different types of cancer cells have been shown to be methionine-dependent. These cells, unlike normal cells, grow poorly or not at all when methionine is replaced by its immediate precursor homocysteine in the growth medium (Met- Hcy+ medium). We have previously shown that apparently normal total amounts of methionine are synthesized by methionine-dependent SV40-transformed human fibroblasts. However, methionine-dependent cells in Met- Hcy+ medium accumulate reduced amounts of S-adenosylmethionine (AdoMet) and elevated amounts of S-adenosylhomocysteine (AdoHcy) that together probably limit growth. In this report, we demonstrate that the amount of free methionine is low in methionine-dependent SV40-transformed human fibroblasts in Met- Hcy+ medium compared to normal human diploid fibroblasts. In contrast, in Met+ Hcy- medium, the amount of free methionine is comparable in both cell types. The deficient pool of free methionine in methionine-dependent cells in Met- Hcy+ medium allows only low amounts of AdoMet to be formed. However, large amounts of the biosynthesized methionine are channeled into protein synthesis. Possible mechanisms are discussed to explain this cancer-associated metabolic defect.

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Reduced availability of endogenously synthesized methionine for S-adenosylmethionine formation in methionine-dependent cancer cells.

Cited by 111 publications

References 15 publications

Expression Profiling of Homocysteine Junction Enzymes in the NCI60 Panel of Human Cancer Cell Lines

Expression Profiling of Homocysteine Junction Enzymes in the NCI60 Panel of Human Cancer Cell Lines

Choline-Deficient-Diet-Induced Fatty Liver Is A Metastasis-Resistant Microenvironment

Reduced free‐methionine in methionine‐dependent SV40‐transformed human fibroblasts synthesizing apparently normal amounts of methionine

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