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 growth of gastric cancer cells derived from the cell line SC-M1. This study was designed to investigate the effect of RA on the sensitivity of SC-M1 cells to lymphokine-activated killer (LAK) activity. RA at the concentration range of 0.001-10 microM was shown to induce SC-M1 cells to exhibit resistance to LAK activity in a dose-dependent manner. A kinetics study indicated that a significantly increased resistance was detected after 2 days of co-culturing SC-M1 cells with RA and reached a maximum after 6 days of culture. Similar results were obtained from two other cancer cell lines: promyelocytic leukaemia HL-60 and hepatic cancer Hep 3B. A binding assay demonstrated that the binding efficacy between target SC-M1 cells and effector LAK cells was not altered by RA. Flow cytometric analyses revealed that RA exhibited no effect on the expression of cell surface molecules, including HLA class I and class II antigens, intercellular adhesion molecule-1 and -2, and lymphocyte function antigen-3. Cell cycle analysis revealed that culture of SC-M1 cells with RA resulted in an increase in G0/G1 phase and a decrease in S phase, accompanied by a decrease in cyclin A and cyclin B1 mRNA as determined by Northern blot analysis. Additionally, RA was shown to enhance the expression of retinoic acid receptor alpha (RAR alpha) in SC-M1 cells, and to have no effect on the expression of RARbeta or RARgamma. Taken together, these results indicate that RA can significantly increase gastric cancer cells SC-M1 to resist LAK cytotoxicity by means of a cytostatic effect through a mechanism relating to cell cycle regulation. The prevailing ideas, such as a decrease in effector to target cell binding, a reduced MHC class I antigen expression or an altered RARbeta expression, are not involved.
Chao
T Y
TY
Department of Medicine, Tri-Service General Hospital, Taipei, Taiwan, Republic of China.
Jiang
S Y
SY
Shyu
R Y
RY
Yeh
M Y
MY
Chu
T M
TM
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D015152:Blotting, Northern; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D016213:Cyclins / Q000096:biosynthesis / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006680:HLA Antigens / Q000096:biosynthesis; D006801:Humans; D016219:Immunotherapy, Adoptive; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology*; D007938:Leukemia / Q000276:immunology / Q000473:pathology; D008113:Liver Neoplasms / Q000276:immunology / Q000473:pathology; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D013274:Stomach Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D015815:Cell Adhesion Molecules; D016213:Cyclins; D006680:HLA Antigens; D018168:Receptors, Retinoic Acid; D014212:Tretinoin