Caudatin Potentiates the Anti-Tumor Effects of TRAIL Against Human Breast Cancer by Upregulating DR5

Phytomedicine. 2019 Sep;62:152950. doi: 10.1016/j.phymed.2019.152950. Epub 2019 May 6.

Abstract

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.

Keywords: CHOP; Caudatin; DR5; MAPK; TRAIL.

MeSH terms

  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis / drug effects
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Female
  • Gene Expression Regulation, Neoplastic
  • Glycosides / pharmacology*
  • Humans
  • MCF-7 Cells
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / genetics
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism*
  • Steroids / pharmacology*
  • TNF-Related Apoptosis-Inducing Ligand / metabolism*
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology
  • Transcription Factor CHOP / genetics
  • Transcription Factor CHOP / metabolism
  • Up-Regulation / drug effects
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Antineoplastic Agents, Phytogenic
  • DDIT3 protein, human
  • Glycosides
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Steroids
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFRSF10B protein, human
  • TNFSF10 protein, human
  • caudatin
  • Transcription Factor CHOP
  • p38 Mitogen-Activated Protein Kinases