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Targeting Autophagy and the Anticipatory Unfolded Protein Response Leads to Increased Breast Cancer Cell Death

Jeffrey Brooks1, Antonina Pizzo1, Caela Fedraw1

  • 1Chemistry & Biochemistry, University of Detroit Mercy, Detroit, Michigan, United States.

Micropublication Biology
|March 10, 2025
PubMed

Insights

The small molecule BHPI triggers cell death in Estrogen Receptor alpha-positive cancer cells by depleting ATP. Combining BHPI with autophagy inhibition significantly enhances this cell death, offering a potential breast cancer therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Biology

Background:

  • The anticipatory unfolded protein response (aUPR) is activated by the small molecule BHPI, inducing necrotic cell death in Estrogen Receptor alpha (ERα)-positive cancer cells.
  • BHPI's mechanism involves the depletion of cellular ATP, a critical energy source for cell survival.

Purpose of the Study:

  • To investigate the role of autophagy in regulating cellular energy levels and ATP production in cancer cells treated with BHPI.
  • To evaluate the efficacy of combining aUPR activation with autophagy inhibition as a therapeutic strategy against ERα-positive breast cancer.

Main Methods:

  • Treatment of T47D and TYS breast cancer cells with BHPI.
  • Assessment of cellular ATP levels and cell death.
  • Modulation of autophagy pathways in conjunction with BHPI treatment.

Main Results:

  • BHPI treatment led to significant ATP depletion and cell death in ERα-positive breast cancer cells.
  • Simultaneous targeting of aUPR and autophagy pathways resulted in a marked increase in cell death compared to BHPI treatment alone.
  • The combination therapy demonstrated enhanced efficacy in T47D and TYS cell lines.

Conclusions:

  • Targeting both aUPR and autophagy pathways represents a promising combination therapeutic strategy for breast cancer.
  • This dual-targeting approach enhances BHPI-induced cell death by further compromising cellular energy levels.
  • Further research into this combination therapy could lead to novel treatment options for ERα-positive breast cancers.

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