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Simultaneous Imaging and Flow-Cytometry-based Detection of Multiple Fluorescent Senescence Markers in Therapy-Induced Senescent Cancer Cells
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An antibiotic that mediates immune destruction of senescent cancer cells

Gabriele Casagrande Raffi1, Jian Chen2, Xuezhao Feng2

  • 1Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands.

Proceedings of the National Academy of Sciences of the United States of America
|December 18, 2024
PubMed

Insights

Senolytics targeting SLC25A23 induce senescent cancer cell death via calcium disruption and PANoptosis. Combining salinomycin with a death receptor 5 antibody enhances immune destruction of senescent cells.

Area of Science:

  • Cellular Biology
  • Cancer Research
  • Immunology

Background:

  • Senescent cells contribute to cancer progression.
  • Senolytics, drugs that eliminate senescent cells, show promise in combination with prosenescence cancer therapies.
  • Identifying novel targets for senolytic drugs is crucial for cancer treatment.

Purpose of the Study:

  • To identify new vulnerabilities in senescent cancer cells.
  • To investigate the mechanism of senescent cell death induced by targeting SLC25A23.
  • To evaluate a novel senolytic drug combination for cancer therapy.

Main Methods:

  • CRISPR/Cas9 genetic screen to identify SLC25A23 as a senescent cell vulnerability.
  • Analysis of cellular calcium homeostasis, oxidative phosphorylation, and redox signaling.
  • Assessment of cell death pathways including apoptosis, necroptosis, and pyroptosis.
  • Investigation of the Jun N-terminal protein kinase (JNK) pathway and reactive oxygen species (ROS) production.
  • Evaluation of a combination therapy using salinomycin and a death receptor 5 (DR5) agonistic antibody.

Main Results:

  • SLC25A23 suppression disrupts calcium homeostasis, impairs oxidative phosphorylation, and interferes with redox signaling, leading to senescent cell death.
  • Salinomycin, a cation ionophore, replicates these effects, inducing pyroptosis-apoptosis-necroptosis (PAN)optosis-like cell death.
  • Salinomycin and SLC25A23 suppression increase ROS, upregulating DR5 via JNK pathway activation.
  • The combination of salinomycin and a DR5 agonistic antibody acts as a potent senolytic cocktail.
  • This combination therapy promotes natural killer (NK) and CD8+ T cell-mediated immune destruction of senescent cancer cells, driven by interleukin 18 (IL18).

Conclusions:

  • SLC25A23 is a critical vulnerability in senescent cancer cells, targeting which leads to cell death through multiple pathways.
  • Salinomycin effectively eliminates senescent cells by inducing PANoptosis and upregulating DR5.
  • The combination of salinomycin and a DR5 agonistic antibody represents a promising senolytic strategy that leverages the immune system for cancer cell destruction.
Keywords:
pyroptosissenescencesenolytics

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