YM155 potently triggers cell death in breast cancer cells through an autophagy-NF-kB network
Eloïse Véquaud1, Céline Séveno1, Delphine Loussouarn1,2
1CRCNA, UMR INSERM U892, CNRS 6299, Université de Nantes, Team 8 « Cell Survival and Tumor Escape in Breast Cancers », Institut de Recherche en Santé de l'Université de Nantes, Nantes, France.
Abstract:
Specific overexpression in cancer cells and evidence of oncogenic functions make Survivin an attractive target in cancer therapy. The small molecule compound YM155 has been described as the first "Survivin suppressant" but molecular mechanisms involved in its biological activity and its clinical potential remain obscure. We herein show that YM155 exerts single agent toxicity on primary breast cancer cells grown in an ex vivo assay preserving tumor microenvironment. In vitro assays indicate that YM155 more efficiently triggers cell death in breast cancer cells (including these with stem-cell like properties) than in non tumorigenic mammary cells. YM155-induced cell death is critically dependent on autophagy and NF-kB but independent of p53 and it coïncides with DNA damage and a DNA damage response in p53-proficient cells. Our results point out a crosstalk between NF-kB and autophagy controlling YM155-induced death in breast cancer cells and argue for the potential use of YM155 as a genotoxic agent in breast cancer therapy.
Insights
The small molecule YM155 shows toxicity against breast cancer cells by inducing cell death. This survivin suppressant relies on autophagy and NF-kB, suggesting potential as a genotoxic cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Survivin is overexpressed in cancer cells, indicating its oncogenic functions.
- Survivin presents an attractive target for cancer therapy.
- The molecular mechanisms and clinical potential of the survivin suppressant YM155 are not fully understood.
Purpose of the Study:
- To investigate the molecular mechanisms underlying YM155's biological activity.
- To evaluate the potential of YM155 as a single agent in breast cancer therapy.
- To explore the role of autophagy and NF-kB in YM155-induced cell death.
Main Methods:
- Ex vivo assay of primary breast cancer cells to assess YM155 toxicity.
- In vitro assays comparing YM155 effects on cancer cells versus non-tumorigenic mammary cells.
- Analysis of YM155-induced cell death pathways, including autophagy, NF-kB, p53, and DNA damage response.
Main Results:
- YM155 demonstrated single-agent toxicity against primary breast cancer cells.
- YM155 induced cell death more effectively in breast cancer cells, including those with stem-cell-like properties, compared to non-tumorigenic cells.
- YM155-induced cell death was dependent on autophagy and NF-kB, but not p53, and was associated with DNA damage and response.
Conclusions:
- A crosstalk between NF-kB and autophagy controls YM155-induced death in breast cancer cells.
- YM155 exhibits potential as a genotoxic agent for breast cancer therapy.
- Further research into YM155's mechanisms and clinical application is warranted.
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