Evidence for Interactions Between Rat Hepatoma Cell Apoptosis and Differentiation

Partial copper depletion of a variant rathepatoma cell line induces a transient inhibition ofgrowth and the genesis of stable, well-differentiatedrevertants. We report a burst of cell death, synchronous with the peak of reversion. The characteristicsof this cell mortality were typical of apoptosis andincluded detachment from the plastic support, chromatincondensation and fragmentation, and internucleosomal DNA degradation. Although commitment to celldeath was induced by copper deficiency, the apoptoticprocess was partially inhibited as assessed fromelectrophoretic patterns of DNA degradation.Redifferentiation was closely linked to the apoptotic deathprogram. Analysis of rescued detached cells in all threemedia (standard, Cu-, Fe-)indicated that the frequency of revertants wassignificantly higher among floating as opposed to adherent cell populations.Nevertheless, experimental copper depletion increased by104 times the revertant frequency amongadherent cells. We propose that redifferentiation of thevariant hepatoma cells (and concomitant recovery oftumorigenicity) is determined by the gene expressionpattern of programmed cell death.