The metabolic defect of methionine dependence occurs frequently in human tumor cell lines

Mecham, James O.; Rowitch, David H.; Wallace, Christine; Stern, P; Hoffman, Robert M.

doi:10.1016/0006-291x(83)91218-4

Cited by 189 publications

(121 citation statements)

References 15 publications

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“…It has been suggested that growth arrest by methionine restriction may be related to the role of methionine as a methyl donor for methylation of DNA, RNA and proteins (Lu and Epner, 2000). Interestingly, normal cells are able to grow in culture when methionine is substituted with homocysteine because mammalian cells can convert homocysteine to methionine (Stern and Hoffman, 1986), but most cancer cells fail to grow in the absence of methionine, even when supplemented with homocysteine (Halpern et al, 1974;Mecham et al, 1983;Stern and Hoffman, 1986), which may result from the elevated levels of transmethylation in cancer cells as compared with normal cells (Tisdale, 1980;Stern and Hoffman, 1984;Judde et al, 1989). It was recently reported that telomeric recombination was elevated by a decrease in methylation of sub-telomeric regions in mouse embryonic stem (ES) cells deficient for DNA Figure 5 Correlation among TRF1, TRF2, TIN2 and RAP1 foci in IIICF/c cells.…”

Section: Discussionmentioning

confidence: 99%

Identification of candidate alternative lengthening of telomeres genes by methionine restriction and RNA interference

et al. 2007

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Telomerase-negative cancer cells can maintain their telomeres by a recombination-mediated alternative lengthening of telomeres (ALT) process. We reported previously that sequestration of MRE11/RAD50/NBS1 complexes represses ALT-mediated telomere length maintenance, and suppresses formation of ALT-associated promyelocytic leukemia (PML) bodies (APBs). APBs are PML bodies containing telomeric DNA and telomere-binding proteins, and are observed only in a small fraction of cells within asynchronously dividing ALT-positive cell populations. Here, we report that methionine restriction caused a reversible arrest in G 0 /G 1 phase of the cell cycle and reversible induction of APB formation in most cells within an ALT-positive population. We combined methionine restriction with RNA interference to test whether the following proteins are required for APB formation: PML body-associated proteins, PML and Sp100; telomereassociated proteins, TRF1, TRF2, TIN2 and RAP1; and DNA repair proteins, MRE11, RAD50, NBS1 and 53BP1. APB formation was not decreased by depletion of Sp100 (as reported previously) or of 53BP1, although 53BP1 partially colocalizes with APBs. Depletion of the other proteins suppressed APB formation. Because of the close linkage between ALT-mediated telomere maintenance and ability to form APBs, the eight proteins identified by this screen as being required for APB formation are also likely to be required for the ALT mechanism.

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Section: Discussionmentioning

confidence: 99%

Identification of candidate alternative lengthening of telomeres genes by methionine restriction and RNA interference

et al. 2007

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“…By contrast, availability of homocysteine does not rescue cancer cells from their methionine dependence. [5][6][7][8] Importantly, remethylation of homocysteine to generate methionine appears to be unaffected in cancer cells. 9 Cancer cell methionine dependency is well-documented.…”

Section: Introductionmentioning

confidence: 99%

“…10 Consistent with a specific effect of methionine restriction non-transformed cells but leads to cell proliferation block in many cancer cells. 6,7,10,11 Relatively little was known about methionine dependency of breast cancer cells. We therefore analyzed growth of various breast cancer cell lines in growth medium with (Met+) or without (Met-Hcy+) methionine (Fig.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of Cdc6 and pre-replication complexes in response to methionine stress in breast cancer cells

et al. 2012

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“…Methionine dependence, the elevated minimal methionine requirement for cell growth relative to normal cells, has been observed in many human cancer cell lines and cancer xenografts in animal models (1)(2)(3)(4)(5). Methionine dependence is a metabolic defect seen only in cancer cells and precludes the cells from growing in media in which methionine is depleted.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics, Methionine Depletion, and Antigenicity of Recombinant Methioninase in Primates

Yang

Wang²,

Yoshioka

et al. 2004

Clinical Cancer Research

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Pharmacokinetics, methionine depletion, antigenicity, and toxicity of recombinant methioninase (rMETase), which has shown efficacy in achieving cell kill in a broad range of human tumor models, were examined in macaque monkeys. Dose-ranging studies at 1000, 2000, and 4000 units/kg i.v. identified the 4000 units/kg dose as able to reduce plasma methionine to an undetectable level (less than 0.5 M) by 30 min, and the level so remained for 8 h. Pharmacokinetic analysis showed that rMETase was eliminated with a T 1/2 of 2.49 h. A 2-week i.v. administration of 4000 units/kg every 8 h/day for 2 weeks resulted in a steady-state depletion of plasma methionine to less than 2 M. The only manifest toxicity was decreased food intake and slight weight loss. Serum albumin and red cell values declined transiently during treatment, which may be related to extensive blood sampling. Re-challenge on day 28 resulted in anaphylactic shock and death in one animal. Subsequent pretreatment with hydrocortisone prevented the anaphylactic reaction, although vomiting was frequently observed. Re-challenge was carried out at days 66, 86, and 116. Anti-rMETase antibodies (at 10 ؊3 ) were found after the first challenge, and these increased to 10 ؊6 after the fourth challenge and decreased to 10 ؊2 by 2 months post therapy. The main rMETase antibody was IgG, and although it has some in vitro features of being a neutralizing antibody, each challenge dose was effective in depleting plasma methionine levels. Thus, rMETase was able to effectively deplete plasma methionine levels with minimal toxicity in a primate model. These data provide the bases for alteration by polyethyleneglycol conjugation (PEGylation) of the enzyme to increase its duration of effect and reduce its immunogenicity.

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The metabolic defect of methionine dependence occurs frequently in human tumor cell lines

Cited by 189 publications

References 15 publications

Identification of candidate alternative lengthening of telomeres genes by methionine restriction and RNA interference

Identification of candidate alternative lengthening of telomeres genes by methionine restriction and RNA interference

Downregulation of Cdc6 and pre-replication complexes in response to methionine stress in breast cancer cells

Pharmacokinetics, Methionine Depletion, and Antigenicity of Recombinant Methioninase in Primates

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