TNF ACCELERATES THE S-PHASE OF THE CELL-CYCLE IN TUMOR-CELLS

The reduction of glucose supply induced the killing of tumor cells by tumor necrosis factor (TNF) in vivo and in vitro. In contrast, normal cell lines were resistant to TNF regardless of the presence or absence of glucose. Epidermal growth factor (EGF) did not exert a cytotoxic e ffect on tumor cells in the absence of glucose. Therefore, the killing mechanism of TNF under conditions of reduced glucose supply was inves tigated. Flow cytometry experiments and studies of kinetics revealed t hat the S-phase of the cell cycle was prolonged in the absence of gluc ose. After TNF treatment, the S-phase was found to be shortened and th e rate of H-3-thymidine incorporation into DNA was increased, whereas EGF failed to exert such an effect. DNA synthesis and entry into mitos is are known to be regulated by cyclin A. In serum-starved tumor cells (HeLa) we have observed increased cyclin A synthesis within 10 hr, in parallel with enhancement of DNA synthesis and shortening of the S-ph ase after TNF treatment. We conclude that, under conditions of low glu cose supply, TNF can assume the role of a growth factor in transformed cells. (C) 1994 Wiley-Liss, Inc.