MODULATION OF RETINOIC ACID RECEPTOR-ALPHA, GROWTH-FACTORS AND PROTOONCOGENES IN RETINOIC ACID-INDUCED APOPTOSIS OF KI-1 LYMPHOMA CELL-LINE

We have previously reported the successful salvage by retinoid acid (RA) of patients with refractory Ki-1 lymphoma. In this study, we have further investigated the effect of all-trans RA on a Ki-1 lymphoma cell line SR786. Similar to the clinical observation, SR786 cells were sensitive to RA treatment (ID50=0.6 mu m). RA-treated SR786 cells were transformed to a more differentiated morphology at 24 h, and subsequently died via apoptosis at 48-72 h. This process was associated with a decreased expression of the proliferation markers and c-myc proto-oncogene. The RA receptor alpha (RAR-alpha), however, showed an immediate enhanced expression at 1/2 h, and followed by an increase of transforming growth factor-beta 1 (TGF-beta 1) gene expression. The apoptosis and increased expression of TGF-beta 1 could be completely blocked;by the addition of cycloheximide given within 12 h of RA treatment. It appears that the RA-induced apoptosis of SR-786 is the result of an RA-induced upregulation of RAR-alpha and a subsequent activation of TGF-beta 1, which in turn leads to a cascade of the suppression of growth-related genes. Our observations strongly support the use of retinoids in Ki-1 lymphoma and invite further studies to test the potential of RA in other specific type T-cell lymphomas.