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

Background: 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.

Purpose: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

CHOP; Caudatin; DR5; MAPK; TRAIL.