Metabolic Aspects of Cell Cycle Regulation in Normal and Cancer Cells

Abstract

Several studies are reviewed dealing with the mechanisms which regulate the cell cycle progression in normal and cancer cells. Using Yoshida AH 130 ascites tumor cells, it has been found that the G1-S transition of these cells is impaired by specific inhibitors of the electron flow through the respiratory chain (antimycin A), although respiratory ATP can be replaced by glycolytic ATP. The above transition can be also inhibited by the addition of physiologic substrates, mainly pyruvate, by a mechanism which appears linked to a modification of the cellular redox state and can be totally reversed by adding adenine to the culture medium. Adenine equally removes the block produced by antimycin A, pointing out a respiration-linked step of purine metabolism restricting the cell recruitment into S. A substantial protection of this step against the inhibitory effects of pyruvate and antimycin A has been obtained by the addition of folate and tetrahydrofolate, suggesting that the respiration-linked limiting step of tumor cell cycling involves folate metabolism and its connection to purine synthesis. The biologic relevance of these findings is stressed by the fact that pyruvate addition also inhibits the proliferation of concanavalin A-stimulated lymphocytes as well as of bone marrow hemopoietic cells in the presence of colony-stimulating factors. On the other hand, pyruvate only slightly affects the growth kinetics of malignant lymphoblasts and of Friend erythroleukemia cells either in the absence or in the presence of the differentiation inducer dimethylsulfoxide.