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CSC-3436 sensitizes triple negative breast cancer cells to TRAIL-induced apoptosis through ROS-mediated

Chun-Chen Huang1, Yi-Ching Cheng1, Ying-Chao Lin2,3,4

  • 1Department of Biological Science and Technology, College of Life Sciences, China Medical University, Taichung, Taiwan.

Environmental Toxicology
|October 2, 2021
PubMed

Insights

This study shows that the flavonoid CSC-3436 sensitizes TRAIL-resistant triple-negative breast cancer cells to apoptosis. It works by upregulating death receptor 5 and downregulating survival proteins.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Tumor necrosis factor-related apoptosis-induced ligand (TRAIL) selectively induces apoptosis in cancer cells but resistance is a clinical challenge.
  • Triple-negative breast cancer (TNBC) often exhibits resistance to TRAIL-mediated apoptosis, necessitating novel therapeutic strategies.
  • Sensitizing agents are crucial to overcome TRAIL resistance and enhance anti-cancer therapy efficacy.

Purpose of the Study:

  • To investigate the efficacy of 2-(3-hydroxyphenyl)-5-methylnaphthyridin-4-one (CSC-3436), a flavonoid, in overcoming TRAIL resistance in TNBC cells.
  • To elucidate the molecular mechanisms by which CSC-3436 sensitizes TNBC cells to TRAIL-induced apoptosis.
  • To explore the role of death receptors and apoptotic pathway proteins in CSC-3436-mediated sensitization.

Main Methods:

  • Treatment of TRAIL-resistant TNBC cells with CSC-3436 and TRAIL.
  • Analysis of death receptor (DR5, DcR1) and decoy receptor expression.
  • Western blot analysis to assess levels of anti-apoptotic (c-FLIPS/L, Bcl-XL, Bcl-2, Survivin, XIAP) and pro-apoptotic (Bax, cleaved Bid) proteins.
  • Investigation of the reactive oxygen species (ROS)/p38/C/EBP-homologous protein (CHOP) signaling pathway.

Main Results:

  • CSC-3436 significantly potentiated TRAIL-induced apoptosis in TRAIL-resistant TNBC cells.
  • CSC-3436 upregulated death receptor 5 (DR5) and downregulated decoy receptor 1 (DcR1) expression.
  • Mechanistically, CSC-3436 decreased anti-apoptotic proteins and increased pro-apoptotic proteins (Bax, cleaved Bid), involving ROS/p38/CHOP signaling for DR5 induction.

Conclusions:

  • CSC-3436 is a promising sensitizing agent for overcoming TRAIL resistance in triple-negative breast cancer.
  • The sensitization mechanism involves modulating the expression of key apoptotic regulators and death receptors.
  • Targeting the ROS/p38/CHOP pathway presents a potential therapeutic strategy to enhance TRAIL-based cancer treatments.
Keywords:
CSC-3436ROSTARILdeath receptortriple negative breast cancer

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