Differential effects of all-trans retinoic acid on the growth of human keratinocytes and mouth carcinoma epidermoid cultures. Role of GRIM-19 and complex I of the respiratory chain

tumor of the oral cavity. A study on the effect of all-trans retinoic acid (RA) on cell growth, expression of GRIM-19 and content and activity of complex I of the mitochondrial respiratory chain in normal human keratinocytes (NHEK) and mouth carcinoma, with low (HN) and high (KB) transformation grade, has been carried out. RA treatment suppressed cell growth of NHEK and HN cells which were brought in Go phase without signs of apoptosis. In these cells RA treatment resulted in overexpression of GRIM-19 protein as constituent subunit of complex I (measured by confocal microscopy and western blot analysis), without transcriptional change (measured by realtime PCR). Despite the increased expression of complex I, we found a depression of the normal NADH-UQ oxidoreductase activity of the complex without any effect on oxygen radicals production. No similar effects of RA were observed in KB mouth carcinoma cells. These data are consistent with the hypothesis that RA could influence the assembly/degradation rate of complex I, but this increased stability of the enzyme could lead to accumulation of “aged” protein with lower functional activity and consequently growth inhibition. In highly transformed KB carcinoma cells this stabilizing effect by RA is override by the higher cellular proteins turnover. These observations provide an insight in the use of RA in the prevention of mouth carcinoma.