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Expression of Methylthioadenosine Phosphorylase cDNA in p16 − , MTAP − Malignant Cells: Restoration of Methylthioadenosine Phosphorylase-Dependent Salvage Pathways and Alterations of Sensitivity to Inhibitors of Purine de novo Synthesis

1997; American Society for Pharmacology and Experimental Therapeutics; Volume: 52; Issue: 5 Linguagem: Inglês

10.1124/mol.52.5.903

1521-0111

Zhihao Chen, Olufunmilayo I. Olopade, Todd M. Savarese,

RNA modifications and cancer

5′-Deoxy-5′-methylthioadenosine phosphorylase (MTAP) is involved in the salvage of adenine and methylthio moieties of 5′-deoxy-5′-methylthioadenosine, a byproduct of polyamine synthesis, to adenine nucleotides and methionine, respectively. The gene encoding MTAP, MTAP , is frequently codeleted along with the tumor suppressor gene p16 in malignant cells bearing homozygous deletions in the chromosome 9p21 region. p16 − , MTAP − malignant cells have been shown to be more susceptible to the purine de novo inhibitory actions of antifolates such as methotrexate than are p16 + , MTAP + cells. To understand the underlying mechanism, we reintroduced MTAP activity into two p16 − , MTAP − cell model systems, the MiaPaCa-2 and PANC-1 human pancreatic carcinoma cell lines, by transfection with MTAP cDNA. It was found that transfection with MTAP cDNA (i) restored both the MTAP-dependent adenine and methionine salvage pathways, (ii) decreased the rates of purine de novo synthesis (18–47% lower than the wild-type or sham-transfected counterparts), and (iii) decreased cellular sensitivity to the antipurine-related growth-inhibitory actions of methotrexate and azaserine. These data support the hypothesis that operation of the MTAP-dependent adenine salvage pathway renders MTAP + cells less dependent on de novo purine synthesis and hence less susceptible than MTAP − malignant cells to the growth-inhibitory actions of agents (e.g. antifolates) whose mechanism of action in part involves the de novo purine pathway. These findings provide a theoretical basis for the relatively selective action certain antifolates may have against MTAP-deficient malignancies.