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.
Highlights
Survivin gene, i.e BIRC5, expression is upregulated in many human tumors and this correlates with metastatic spread, tumor invasiness, and poor prognosis associated with treatment resistance
Consistent with previous reports, we further observe that the autophagy process delineates YM155-induced cell death in a p53independent way despite DNA damage occurence, but we demonstrate that the canonical NF-kB pathway potently controls YM155-induced cell death, upstream the autophagy process
The small molecule YM155 came out of a high-throughput screening for inhibitors of BIRC5 promoter activity and phase I clinical trials using this compound, conducted in heavily pretreated cancer patients provided evidence that an objective tumor response could be achieved in some cases with an overall favorable toxicity profile
Summary
I.e BIRC5, expression is upregulated in many human tumors and this correlates with metastatic spread, tumor invasiness, and poor prognosis associated with treatment resistance. YM155 has been demonstrated to exert antitumor activity, to suppress Survivin expression and to induce tumor cell apoptosis, in various human cancer models. It has already completed phase 2 clinical trials for various kinds of cancers which validates its safety [reviewed in 2]. Deregulation of both pathways is frequently observed and is associated with tumorigenesis and tumor cell resistance to cancer therapies [4, 5] Both are induced under cellular stress and ensure homeostatic responses in controlling each other through positive or negative feedback loops. Our results point out for the first time that YM155 induces cell death in primary human breast cancer cells and that a NF-kB and autophagy network controls its activity
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