Expression profiling of homocysteine junction enzymes in the NCI60 panel of human cancer cell lines.
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 beta-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.
Zhang
Wen
W
Department of Biochemistry, University of Nebraska, Lincoln, Nebraska, USA.
Braun
Aaron
A
Bauman
Zachary
Z
Olteanu
Horatiu
H
Madzelan
Peter
P
Banerjee
Ruma
R
D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000096:biosynthesis / Q000235:genetics; D045744:Cell Line, Tumor; D003541:Cystathionine beta-Synthase / Q000096:biosynthesis / Q000235:genetics; D005287:Ferredoxin-NADP Reductase / Q000096:biosynthesis / Q000235:genetics; D020869:Gene Expression Profiling; D006710:Homocysteine / Q000378:metabolism*; D006801:Humans; D008715:Methionine / Q000378:metabolism*; D009251:NADPH-Ferrihemoprotein Reductase / Q000096:biosynthesis / Q000235:genetics; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics
D006710:Homocysteine; D008715:Methionine; C111241:methionine synthase reductase; D005287:Ferredoxin-NADP Reductase; D009251:NADPH-Ferrihemoprotein Reductase; D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; D003541:Cystathionine beta-Synthase