D-allose suppresses colitis associated carcinogenesis by reversing ER stress in macrophages and inhibiting cancer cell proliferation.

INTRODUCTION: Inflammatory bowel diseases (IBD), especially ulcerative colitis, are associated with a high risk of carcinogenesis. D-allose, a D-glucose epimer, exhibits antioxidant and antitumor activities. This study aimed to examine the effects of D-allose on colitis-associated carcinogenesis. METHODS: A mouse model of colitis-associated carcinogenesis was established followed by treatment with D-allose. In vitro, ER stress and mitochondrial function in RAW 264.7 macrophages and the migration and proliferation of Caco-2 cells were analyzed to elucidate the underlying mechanisms. Colonic tissues obtained from IBD patients with were subjected to analyze ER stress in macrophages. RESULTS: D-allose administration significantly reduced the tumor number, hemorrhage, inflammation score, and macrophage infiltration in the AOM/DSS model. D-allose suppressed ER stress signal and mitochondrial dysfunction in LPS treated RAW 264.7 macrophages. D-allose suppressed ER stress marker Bip and CHOP expression in thapsigargin treated RAW 264.7. In IBD patient's colon, ER stress marker Bip and CHOP positive macrophage infiltration was detected in both inflammatory and tumor areas. The level of fluorescence labeled M6~G1M9 oligosaccharides increased in the LPS-treated RAW 264.7 macrophages, while thapsigargin or D-allose had no effect. In Caco-2 cells, D-allose suppressed phosphorylated AMPK expression, reduced migratory activity. D-allose inhibited glycolysis, and decreased cell proliferation through TXNIP upregulation. CONCLUSION: D-allose suppressed inflammation and tumor development in a colitis-associated carcinogenesis model. D-allose restoring macrophage ER stress and mitochondrial dysfunction, and inhibiting colon cancer cell migration and proliferation. Therefore, D-allose may represent as a promising therapeutic and preventive agent for IBD and inflammation-associated carcinogenesis.