ALL-TRANS-RETINOIC ACID DECREASES SUSCEPTIBILITY OF A GASTRIC-CANCER CELL-LINE TO LYMPHOKINE-ACTIVATED KILLER CYTOTOXICITY

All-trans retinoic acid (RA) was previously shown to regulate the grow th of gastric cancer cells derived from the cell line SC-M1. This stud y was designed to investigate the effect of RA on the sensitivity of S C-M1 cells to lymphokine-activated killer (LAK) activity. RA at the co ncentration range of 0.001-10 mu M was shown to induce SC-M1 cells to exhibit resistance to LAK activity in a dose-dependent manner. A kinet ics study indicated that a significantly increased resistance was dete cted after 2 days of co-culturing SC-M1 cells with RA and reached a ma ximum after 6 days of culture. Similar results were obtained from two other cancer cell lines: promyelocytic leukaemia HL-60 and hepatic can cer Hep 3B. A binding assay demonstrated that the binding efficacy bet ween target SC-MI cells and effector LAK cells was not altered by RA. Flow cytometric analyses revealed that RA exhibited no effect on the e xpression of cell surface molecules, including HLA class I and class I I antigens, intercellular adhesion molecule-1 and -2, and lymphocyte f unction antigen-3. Cell cycle analysis revealed that culture of SC-M1 cells with RA resulted in an increase in G(0)/G(1) phase and a decreas e in S phase, accompanied by a decrease in cyclin A and cyclin B1 mRNA as determined by Northern blot analysis. Additionally, RA was shown t o enhance the expression of retinoic acid receptor alpha (RAR alpha) i n SC-M1 cells, and to have no effect on the expression of RAR beta or RAR gamma. Taken together, these results indicate that RA can signific antly increase gastric cancer cells SC-M1 to resist LAK cytotoxicity b y means of a cytostatic effect through a mechanism relating to cell cy cle regulation. The prevailing ideas, such as a decrease in effector t o target cell binding, a reduced MHC class I antigen expression or an altered RAR beta expression, are not involved.