TNF down-regulation of receptor tyrosine kinase-dependent mitogenic signalpathways as an important step in cytostasis induction and commitment to apoptosis of Kym-1 rhabdomyosarcoma cells

Growth of Kym-1 rhabdomyosarcoma cells depends on endogenous receptor tyros ine kinase signals activated by insulin and insulin-like growth factors (IG F), as revealed from enhancement of proliferation by insulin and IGF-1 and cytostatic action of inhibitors of IR/IGFR kinases, Depending on the presen ce or absence of the caspase inhibitor z-VAD-fmk, TNF induced full growth a rrest or apoptosis, respectively, indicating dominance of TNF over mitogeni c signal pathways in Kym-1 cells, In accordance with a caspase independent cytostatic action, TNF downregulated IR kinase activity and caused a profou nd inhibition of downstream mitogenic signals including the MAPK cascade an d STAT5, key pathways of proliferation and cell survival. Removal of z-VAD- fmk after 24 h induced rapid cell death in the absence of TNF, The inhibiti on of survival signals concomitant with persisting proapoptotic signals may tip the balance towards an irreversible commitment of the cell to apoptosi s that becomes apparent upon relief of suppression of effector caspases.