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Caudatin potentiates the anti-tumor effects of TRAIL against human breast cancer by upregulating DR5

Fei, Hong-rong, Yuan, Chuang, Wang, Gui-ling, Zhao, Ying, Li, Zhao-jun, Du, Xin, Wang, Feng-Ze
Phytomedicine 2019 v.62 pp. 152950
Cynanchum, Western blotting, antineoplastic activity, apoptosis, breast neoplasms, cell cycle, death domain receptors, flow cytometry, glycosides, growth retardation, humans, ligands, mitogen-activated protein kinase, necrosis, neoplasm cells, phosphorylation, propidium, protein synthesis, roots, staining, therapeutics
The ability of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to preferentially induce apoptosis in transformed cells while sparing most normal cells is well established. However, the intrinsic and acquired resistance of tumors to TRAIL-induced apoptosis limits its therapeutic applicability.We investigated the effect of caudatin, a species of C-21 steroidal glycosides isolated from the roots of Cynanchum auriculatum, on TRAIL-induced apoptosis in human breast cancer cells.Cell growth inhibition was evaluated by the CCK-8 assay. The cell cycle distribution was assessed by propidium iodide flow cytometry. Apoptosis was determined by TUNEL staining. Protein expression was detected by western blotting analysis.Caudatin enhanced TRAIL-induced apoptosis in human breast cancer cells. This sensitization was achieved by upregulating death receptor 5 (DR5). Knockdown of DR5 abolished the enhancing effect of caudatin on TRAIL responses. The caudatin-induced upregulation of DR5 was accompanied by increased expression of CHOP and phosphorylation of p38 MAPK and JNK. CHOP knockdown blocked caudatin-upregulated DR5 expression. Moreover, cotreatment of breast cancer cells with p38 MAPK and JNK inhibitors significantly counteracted the caudatin-induced expression of DR5.Our results showed that caudatin sensitized breast cancer cells to TRAIL-induced apoptosis through activation of CHOP, p38 MAPK and JNK-mediated upregulation of DR5 expression. The combination of TRAIL and caudatin may be a promising therapeutic approach for the treatment of breast cancer.