Abstract 2495: Glucosamine enhances TRAIL-induces apoptosis in DU145 and Hela cancer cell lines

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has attracted wide attention and extensive research because of selective apoptosis of tumor cells but not of normal cells. However, the clinical trials using TRAIL alone were disappointed due to the resistance of cancer cells to the TRAIL-treatment. Several resistant mechanisms, such as low expression of death receptors, and overexpression of cFLIP, BCL-2 antiapoptotic family members and XIAP were proposed. Tunicamycin was reported to enhance the expression of death receptor 5 through the activation of CHOP. Similar to tunicamycin, glucosamine is known to increase the expression of CHOP by inducing ER stress. We thus investigated whether glucosamine could increase the expression of death receptor 5 to overcome TRAIL-resistance. We found that glucosamine treatment of DU145 cells did not increase the expression of death receptor 5 on the cell surface, even though the overall expression was increased. However, glucosamine significantly increased TRAIL-induced apoptosis in DU145 and Hela cells. Our investigation revealed that glucosamine sensitized cancer cells to TRAIL-induced apoptosis through both intrinsic and extrinsic apoptosis pathways, as evidenced by the cleavage of both caspase 9 and caspase 8. Our data further showed that the combination of TRAIL with glucosamine suppressed the expression of cFLIP, BCL-2 and XIAP, translocated BAK to the mitochondrial outer membrane, and released cytochrome C and SMAC from mitochondrial. Interestingly, in addition to the activation of apoptotic pathways, TRAIL-mediated inflammatory responses were attenuated by glucosamine treatment. Pretreatment of glucosamine reduced the TRAIL-induced nuclear NF-kB level and the expression of IL-6 and IL-8. Together, these results demonstrated that the combination treatment, TRAIL with glucosamine, may provide a promising novel strategy for treating different human cancers by overcoming TRAIL-resistance and inhibiting TRAIL-induced inflammation. Citation Format: Chao Sun, Viktor Chesnokov, Keiichi Itakura. Glucosamine enhances TRAIL-induces apoptosis in DU145 and Hela cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2495.