High sensitivity of human melanoma cell lines to the growth inhibitory activity of mycoplasmal arginine deiminase in vitro

Sugimura, Kazuyuki; Ohno, Tadao; Kusuyama, T; Azuma, Ichiro

doi:10.1097/00008390-199209000-00007

Cited by 80 publications

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“…The third melanoma line, G361, could survive in citrulline but showed little or no real growth, indicating a very low maintenance level of argininosuccinate synthetase. It therefore has almost total dependence on arginine, also in accord with the data of Sugimura et al (1992).…”

Section: Cell Differences In Citrulline and Argininosuccinate Utilisasupporting

confidence: 87%

“…Fibroblasts have the ability to use citrulline, and their behaviour is consistent with tight coupling of the citrulline-arginine pathway (Cheung et al, 1989;Schimke, 1964) because of their complete inability to handle argininosuccinate in the absence of citrulline. The melanoma data in Table 1 are in accord with Sugimura et al (1992) findings in melanomas; our data confirm that two of them were unable to metabolise citrulline (A375 and MEWO), but that they could grow in argininosuccinate-supplemented medium. The third melanoma line, G361, could survive in citrulline but showed little or no real growth, indicating a very low maintenance level of argininosuccinate synthetase.…”

Section: Cell Differences In Citrulline and Argininosuccinate Utilisasupporting

confidence: 85%

“…Ensor et al (2002) found a complete absence of argininosuccinate synthetase in both human melanoma and hepatocellular carcinoma cell lines. The fact that close to half of all tumour cell types given in Table 1 failed to convert citrulline seems a high percentage to us, even when we know that these other investigators confined themselves to melanomas and hepatocellular carcinomas (Sugimura et al, 1992;Ensor et al, 2002). However, the latter authors do concede that several different tumour cells types are not inhibited so strongly by arginine deprivation and can use citrulline, although they furnished no actual data on them other than their designations.…”

Section: Cell Differences In Citrulline and Argininosuccinate Utilisamentioning

confidence: 85%

“…This makes it difficult to understand how previous in vivo work with arginase and arginine deiminase could have achieved significant inhibition of tumour growth under similar conditions (Bach and Swaine, 1965;Miyazaki et al, 1990), and begs further analysis of the ability of tumour cells to use citrulline in lieu of arginine (Wheatley and Campbell, 2002). Sugimura et al (1992) found that four out of five human melanoma cell lines deprived of arginine with arginine deiminase (EC 3.5.3.6) could not be rescued with citrulline, but grew when argininosuccinate, the immediate downstream intermediate, was supplied. Another tumour type that is characteristically deficient in this enzyme is human hepatocellular carcinoma (Ensor et al, 2002).…”

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confidence: 99%

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Arginine deprivation, growth inhibition and tumour cell death: 3. Deficient utilisation of citrulline by malignant cells

Wheatley

Campbell

2003

Br J Cancer

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Arginine deprivation causes death of up to 80% of cancer cell lines in vitro, but in the body, citrulline would be available as a convertible source of this amino acid in vivo. Some tumour cell lines, notably the vast majority of melanomas and hepatocellular carcinomas, tend to be deficient in argininosuccinate synthetase (EC 6.5.4.3.), and therefore cannot recycle citrulline to arginine. Argininosuccinate synthetase is present at levels that convert enough citrulline to arginine to allow limited growth in about half of a modest range of malignant cell types analysed in this study. Attempts to rescue cells that are unable to utilise citrulline with the immediate downstream product, argininosuccinate, had very limited success in a few tumour cell lines. Particularly noteworthy is the demonstration that argininosuccinate was totally incapable of rescuing cells that utilise citrulline efficiently, consistent with tight channelling (coupling) of argininosuccinate synthetase and argininosuccinate lyase in the urea cycle. The findings suggest that an excellent opportunity exists for further exploitation of arginine deprivation in the selective killing of tumour cells. Arginine is a vital amino acid for many metabolic processes other than protein synthesis (e.g. creatine production, polyamine synthesis and nitric oxide (NO) generation). Its removal from culture medium by medium formulation or arginase treatment quickly leads to death in B80% of tumour cell lines (Scott et al, 2000). The addition of citrulline can often circumvent this deficiency, but few cells are capable of its biosynthesis in culture. Arginine deficiency in vivo has been induced by various means, but is less effectively achieved because body homeostasis is too robust, and citrulline generation is difficult to control. Having successfully reduced L1210 cells in culture to negligible viability in 3-5 days with arginase (EC 3.5.3.1), citrulline supplementation in the continued presence of the enzyme partially circumvented the arginine deficiency. The rate of conversion became a rate-limiting factor, most noticeably in such fast-growing leukaemia as L1210 (Philip et al, 2003). In a corresponding in vivo study, arginase treatment of DBA/2 mice injected intraperitoneally with 1210 cells increased neither their survival time nor decreased tumour burden, despite plasma arginine falling to B1-2 mM level. Plasma citrulline remained normal, and therefore the tumour cells must have converted citrulline to arginine fast enough to sustain relatively normal tumour growth rate (Wu and Morris, 1998;Philip et al, 2003). This makes it difficult to understand how previous in vivo work with arginase and arginine deiminase could have achieved significant inhibition of tumour growth under similar conditions (Bach and Swaine, 1965;Miyazaki et al, 1990), and begs further analysis of the ability of tumour cells to use citrulline in lieu of arginine (Wheatley and Campbell, 2002). Sugimura et al (1992) found that four out of five human melanoma cell lines deprived of arginine w...

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Section: Cell Differences In Citrulline and Argininosuccinate Utilisasupporting

confidence: 87%

Section: Cell Differences In Citrulline and Argininosuccinate Utilisasupporting

confidence: 85%

Section: Cell Differences In Citrulline and Argininosuccinate Utilisamentioning

confidence: 85%

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confidence: 99%

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Arginine deprivation, growth inhibition and tumour cell death: 3. Deficient utilisation of citrulline by malignant cells

Wheatley

Campbell

2003

Br J Cancer

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“…The conversion of ornithine to citrulline requires ornithine carbamoyl transferase (OCT; EC 2.1.3.3), but apart from normal hepatocytes and a few minimal deviation hepatomas, most cultured cells cannot perform this transfer (Sugimura et al, 1992), and therefore ornithine rarely substitutes for arginine in culture (Eagle, 1955). On the other hand, Eagle (1959) found that citrulline can substitute for arginine, and this is so in all malignant and normal cells cultured in aegininefree medium (AFM) that we have so far investigated .…”

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confidence: 99%

Arginine deprivation, growth inhibition and tumour cell death: 2. Enzymatic degradation of arginine in normal and malignant cell cultures

2003

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Arginase added to culture medium reduced arginine to negligible levels within B6 h, and enzyme activity persisted relatively undiminished for at least 3 days. Human and bovine arginase proved equally effective. The response of normal cells was to enter G1 (G0) arrest, from which most of the cells could be recovered weeks later. In contrast, malignant cell lines treated with unpegylated or pegylated enzyme resulted in cell death on a massive scale within 3 -5 days, with a very low to negligible percentage of cells (o0.01%) being recoverable on restoration with arginine. Although pegylation resulted in a 40% drop in specific activity, arginase was considerably more stable and remained active for b8 days. Arginine decarboxylase caused malignant cell arrest at the same units per millilitre as arginase. Its breakdown product, agmatine, was relatively nontoxic in the presence of arginine, but exacerbated cell death above millimolar concentration in its absence. Although ornithine failed to rescue cells from deprivation, citrulline recovered cells in all cases, although less well in fast-growing tumour cell populations, whereas readdition of arginine failed to work unless a complete medium change was given (because of the persistence of the enzymes in the medium catabolising its destruction). The advantages and disadvantages of these two arginine-catabolising enzymes are discussed, and compared with arginine deiminase.

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Identification of Tumor-Suppressor Genes Using Human Melanoma Cell Lines UACC903, UACC903(+6), and SRS3 by Comparison of Expression Profiles

Bittner

Chen

et al. 2000

Mol. Carcinog.

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The development and progression of cancer are believed to be due to multiple genetic alterations resulting in complex changes in expression of many genes. The parental malignant melanoma cell line UACC903 displays anchorage‐independent growth, and the chromosome 6–suppressed subline UACC903(+6) displays anchorage‐dependent growth. The anchorage‐independent revertant cell line SRS3 derived from UACC903(+6) by retroviral transduction resembles the phenotype of UACC903. In this study, we first compared the expression profiles of 3317 genes between these three cell lines in pairs by cDNA microarrays, resulting in identification of genes with known suppressor activities. We then demonstrated connexin 43 (C×43)–suppressing anchorage‐independent growth of UACC903 on overexpression. Of 3317 genes with informative expression detected by cDNA microarray, 321 (9.68%) showed expression changes between at least one pair of the three cell lines. Notably, 12 genes displayed higher levels of expression in UACC903(+6) than in both UACC903 and SRS3, providing candidates for further identification of melanoma‐suppressor genes. Genes encoding C×43 (suppressor activity), monocyte chemotactic protein 1 (suppressor activity), and cysteine proteinase P32α (apoptotic activity) were all upregulated in UACC903(+6), in contrast to both UACC903 and SRS3. Transfection of C×43, encoded on human chromosome 6q21–q23, a region frequently altered in malignant melanoma, resulted in its overexpression and the suppression of anchorage‐independent growth of UACC903. Thus, our result proves the principle that the combination of the ability to alter cellular phenotype by successive genetic alterations and the ability to examine the global expression profiles facilitates the identification of tumor suppressor genes. Mol. Carcinog. 28:119–127, 2000. © 2000 Wiley‐Liss, Inc.

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High sensitivity of human melanoma cell lines to the growth inhibitory activity of mycoplasmal arginine deiminase in vitro

Cited by 80 publications

References 0 publications

Arginine deprivation, growth inhibition and tumour cell death: 3. Deficient utilisation of citrulline by malignant cells

Arginine deprivation, growth inhibition and tumour cell death: 3. Deficient utilisation of citrulline by malignant cells

Arginine deprivation, growth inhibition and tumour cell death: 2. Enzymatic degradation of arginine in normal and malignant cell cultures

Identification of Tumor-Suppressor Genes Using Human Melanoma Cell Lines UACC903, UACC903(+6), and SRS3 by Comparison of Expression Profiles

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