Retinoic acid-induced downmodulation of telomerase activity in human cancer cells

Abstract

Most human cancers express telomerase but its activity is highly variable and regulated by complex mechanisms. Recently, several studies have suggested that retinoic acid (RA) downregulates telomerase activity and that this effect could be a major determinant of its therapeutic activity. To elucidate possible mechanisms of RA-mediated downmodulation of telomerase activity, we measured the kinetics of concentration changes of several transcription regulators by using standard biochemical techniques at low (10 μM) and high (100 μM) RA concentrations. We further evaluated the global impact of the RA treatment on gene expression profiles using microarray. It was found that the kinetics of c-Myc correlates most closely with the telomerase activity suggesting in agreement with previous studies that this protein is a major intermediate of the RA-induced downregulation of telomerase activity. Other telomerase regulators as Sp1 and Mad1 did not exhibit significant correlation. The dominant role of c-Myc in RA-induced telomerase downmodulation is confirmed by microarray data. Additionally, a number of proteins were found as possible correlates of telomerase activity by microarray analysis. These data suggest a complex interplay between c-Myc and other proteins that may be important determinants of the RA effects on telomerase activity in human cancer cells. The complex mechanism through which telomerase activity is controlled during differentiation and cancer transformation is also reflected.