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Highly expressed SERCA2 triggers tumor cell autophagy and is a druggable vulnerability in triple-negative breast

Minmin Fan1,2, Jian Gao1, Lin Zhou1

  • 1State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing 210023, China.

Acta Pharmaceutica Sinica. B
|December 23, 2022
PubMed

Insights

Triple negative breast cancer (TNBC) cells use SERCA2 to promote growth and chemoresistance via autophagy. Targeting SERCA2 with RL71 induces cell death, offering a new therapeutic strategy for TNBC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Chemoresistance is a significant challenge in treating triple-negative breast cancer (TNBC).
  • Identifying new therapeutic targets is crucial for effective TNBC treatment.
  • SERCA2 expression is linked to TNBC progression.

Purpose of the Study:

  • To investigate the role of SERCA2 in TNBC progression and chemoresistance.
  • To elucidate the mechanism by which SERCA2 influences autophagy in TNBC.
  • To evaluate SERCA2 as a potential therapeutic target for TNBC.

Main Methods:

  • Correlation analysis of SERCA2 expression with TNBC patient data.
  • Investigation of SERCA2-LC3B interaction and its role in autophagy.
  • Assessment of RL71 effects on SERCA2-targeting and autophagic cell death in vitro and in vivo.

Main Results:

  • SERCA2 expression correlates with TNBC progression, enhancing proliferation, migration, and chemoresistance.
  • SERCA2 interacts with LC3B, promoting WIPI2-independent autophagosome formation and autophagy.
  • Autophagy-mediated SERCA2 degradation triggers a Ca2+/CaMKK/CREB-1 feedback loop.
  • The small molecule RL71 enhances SERCA2-LC3B interaction, inducing excessive autophagic cell death.
  • Increased SERCA2 expression sensitizes TNBC cells to RL71-induced autophagic cell death.

Conclusions:

  • TNBC cells utilize high autophagy activity, driven by SERCA2, to achieve chemoresistance.
  • Increased SERCA2 expression represents a druggable vulnerability in TNBC.
  • Targeting SERCA2 with RL71 offers a promising therapeutic strategy for TNBC treatment.
Keywords:
AutophagyChemoresistanceDruggableLC3BSERCA2TNBCVulnerability

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