Abstract
Cancer cells have an elevated methionine (MET) requirement compared to normal cells and are termed MET dependent. Cancer cells were isolated in MET-restricted (MR) medium that reverted from MET dependence to MET independence. Increased MET biosynthesis was not a prerequisite for reversion to MET independence, indicating that MET dependence was not due to reduced endogenous MET synthesis. MET-independent revertants of cancer cells concomitantly reverted for some of the other properties associated with malignancy: Of the 13 MET-independent revertants isolated 5 showed increased anchorage dependence as reflected by reduced cloning efficiencies in methylcellulose; 8 showed an increased serum requirement for optimal growth; 8 showed decreased cell density in medium containing high serum; and 3 altered their cell morphology significantly. Eight of the 13 revertants have increased chromosome numbers. Thus, by selecting for MET independence, it is possible to obtain heterogeneous reduced-malignancy revertants, indicating further a relationship between altered MET metabolism and other fundamental properties of oncogenic transformation.
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References
Hoffman RM (2015) Development of recombinant methioninase to target the general cancer-specific metabolic defect of methionine dependence: a 40-year odyssey. Expert Opin Biol Ther 15:21–31
Hoffman RM, Erbe RW (1976) High in vivo rates of methionine biosynthesis in transformed human and malignant rat cells auxotrophic for methionine. Proc Natl Acad Sci U S A 73:1523–1527
Hoffman RM, Jacobsen SJ, Erbe RW (1978) Reversion to methionine independence by malignant rat and SV40-transformed human fibroblasts. Biochem Biophys Res Commun 82:228–234
Stern PH, Hoffman RM (1984) Elevated overall rates of transmethylation in cell lines from diverse human tumors. In Vitro 20:663–670
Xu W, Gao L, Shao A, Zheng J, Zhang J (2017) The performance of 11C-methionine PET in the differential diagnosis of glioma recurrence. Oncotarget 8:91030–91039
Murakami T, Li S, Han Q, Tan Y, Kiyuna T, Igarashi K, Kawaguchi K, Hwang HK, Miyaki K, Singh AS, Hiroshima Y, Lwin TM, DeLong JC, Chishima T, Tanaka K, Bouvet M, Endo I, Eilber FC, Hoffman RM (2017) Recombinant methioninase effectively targets a Ewing’s sarcoma in a patient-derived orthotopic xenograft (PDOX) nude-mouse model. Oncotarget 8:35630–35638
Warburg O (1956) On the origin of cancer cells. Science 123:309–314
Hoffman RM, Jacobsen SJ, Erbe RW (1979) Reversion to methionine independence in simian virus 40-transformed human and malignant rat fibroblasts is associated with altered ploidy and altered properties of transformation. Proc Natl Acad Sci U S A 76:1313–1317
Kamely D, Littlefield JW, Erbe RW (1973) Regulation of 5-methyltetrahydrofolate: homocysteine methyltransferase activity by methionine, vitamin B12, and folate in cultured baby hamster kidney cells. Proc Natl Acad Sci USA 70:2585–2589
Rosenblatt DS, Erbe RW (1973) Reciprocal changes in the levels of functionally related folate enzymes during the culture cycle in human fibroblasts. Biochem Biophys Res Commun 54:1627–1633
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275
Black PH, Rowe WP, Turner HC, Huebner RJ (1963) A specific complement-fixing antigen present in SV40 tumor and transformed cells. Proc Natl Acad Sci U S A 50:1148–1156
Judde JG, Ellis M, Frost P (1989) Biochemical analysis of the role of transmethylation in the methionine dependence of tumor cells. Cancer Res 49:4859–4865
Freedman VH, Shin SI (1974) Cellular tumorigenicity in nude mice: correlation with cell growth in semi-solid medium. Cell 3:355–359
Osborn M, Weber K (1975) Simian virus 40 gene A function and maintenance of transformation. J Virol 15:636–644
Pollack R, Wolman S, Vogel A (1970) Reversion of virus-transformed cell lines: hyperploidy accompanies retention of viral genes. Nature 228(5275):938
Weiss MC (1970) Further studies on loss of T-antigen from somatic hybrids between mouse cells and SV40-transformed human cells. Proc Natl Acad Sci U S A 66(1):79–86
Bloomfield M, Duesberg P (2015) Karyotype alteration generates the neoplastic phenotypes of SV40-infected human and rodent cells. Mol Cytogenet 8:79
Yamamoto T, Rabinowitz Z, Sachs L (1973) Identification of the chromosomes that control malignancy. Nat New Biol 243:247–250
Vanhamme L, Szpirer C (1989) Spontaneous and 5-azacytidine-induced revertants of methionine-dependent tumor-derived and H-ras-1-transformed cells. Exp Cell Res 181:159–168
Vanhamme L, Szpirer C (1987) Methionine metabolism defect in cells transfected with an activated HRAS1 oncogene. Exp Cell Res 169:120–126
St. Croix B, Flørenes VA, Rak JW, Flanagan M, Bhattacharya N, Slingerland JM, Kerbel RS (1996) Impact of the cyclin-dependent kinase inhibitor p27Kip1 on resistance of tumor cells to anticancer agents. Nat Med 2:1204–1210
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Hoffman, R.M., Erbe, R.W. (2019). Linkage of Methionine Dependence and Other Features of Malignancy. In: Hoffman, R. (eds) Methionine Dependence of Cancer and Aging. Methods in Molecular Biology, vol 1866. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-8796-2_3
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DOI: https://doi.org/10.1007/978-1-4939-8796-2_3
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