EVIDENCE FOR INTERACTIONS BETWEEN RAT HEPATOMA-CELL APOPTOSIS AND DIFFERENTIATION

Partial copper depletion of a variant rat hepatoma cell line induces a transient inhibition of growth and the genesis of stable, well-differ entiated revertants. We report a burst of cell death, synchronous with the peak of reversion. The characteristics of this cell mortality wer e typical of apoptosis and included detachment from the plastic suppor t, chromatin condensation and fragmentation, and internucleosomal DNA degradation. Although commitment to cell death was induced by copper d eficiency, the apoptotic process was partially inhibited as assessed f rom electrophoretic patterns of DNA degradation. Redifferentiation was closely linked to the apoptotic death program. Analysis of rescued de tached cells in all three media (standard, Cu-, Fe-) indicated that th e frequency of revertants was significantly higher among floating as o pposed to adherent cell populations. Nevertheless, experimental copper depletion increased by 10(4) times the revertant frequency among adhe rent cells. We propose that redifferentiation of the variant hepatoma cells (and concomitant recovery of tumorigenicity) is determined by th e gene expression pattern of programmed cell death.