Methionine adenosyltransferase (MAT) is an essential enzyme in metabolism because It catalyzes the synthesis of S-adenosylmethionine (AdoMet, SAMe), a pivotal biological molecule that functions as the major methyl donor and a precursor for homocysteine and the polyamines. AdoMet is second only to ATP in the number of reactions it participates in, or regulates. Methylation reactions regulate the function and activity of proteins, nucleic acids and lipids. Studies have shown that abnormal AdoMet levels (high or low) are associated with malignant transformations and that aberrant biological methylation can lead to cancer by affecting gene expression, RNA stability, protein function, as well as cell growth and differentiation. Because of its central role in metabolism, the synthesis of AdoMet by MAT has been targeted for inhibition by chemical drugs for years. We have used MAT inhibitors to block the growth and differentiation of human T cells, and others have shown that inhibition of AdoMet synthesis in cancer cells, including leukemic cells, significantly reduced their growth. The problem was that MAT chemical inhibitors were very difficult to synthesize in large quantities, and most were reversible and nonspecific. Our studies to date have led us to propose that AdoMet levels can be potentiated in leukemic T cells by using molecular tools that modulate the expression of MAT subunits. This application focuses on the development of these tools and the assessment of their effect in diminishing the growth of leukemic cells. We have demonstrated that MAT regulation and AdoMet metabolism are drastically different in normal and leukemic T cells. The central hypothesis is that we can exploit these physiological differences and selectively modulate AdoMet metabolism in leukemic cells in a way that halts their growth. We propose that this can be affected by potentiating the expression of the regulatory ? subunit of the MAT II isozyme, the only isozyme of MAT found in extrahepatic tissue. ? ?
| Attia, Ramy R; Gardner, Lidia A; Mahrous, Engy et al. (2008) Selective targeting of leukemic cell growth in vivo and in vitro using a gene silencing approach to diminish S-adenosylmethionine synthesis. J Biol Chem 283:30788-95 |
