Blockade of NFκB activity by Sunitinib increases cell death in Bortezomib-treated endometrial carcinoma cells

Anabel Sorolla Bardaji, Andree Yeramian, Joan Valls, Xavier Dolcet, Laura Bergada, Antoni Llombart-Cussac, Rosa Maria Marti, Xavier Matias-Guiu

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29 Citations (Scopus)

Abstract

Endometrial carcinoma is one of the most common malignancies in the female genital tract, usually treated by surgery and radiotherapy. Chemotherapy is used when endometrial carcinoma is associated with widespread metastasis or when the tumor recurs after radiation therapy. In the present study, we demonstrate that the tyrosine kinase receptor inhibitor Sunitinib reduces cell viability, proliferation, clonogenicity and induces apoptotic cell death in endometrial carcinoma cell lines, which is not due to its action through the most known targets like VEGFR, nor through EGFR as demonstrated in this work. Interestingly, Sunitinib reduces NF kappa B transcriptional activity either at basal level or activation by EGF or TNF-alpha. We observed that Sunitinib was able to inhibit the Bortezomib-induced NF kappa B transcriptional activity which correlates with a decrease of the phosphorylated levels of IKK alpha and beta, p65 and I kappa B alpha. We evaluated the nature of the interaction between Sunitinib and Bortezomib by the dose effect method and identified a synergistic effect (combination index <1). Analogously, silencing of p65 expression by lentiviral-mediated short-hairpin RNA delivery in Bortezomib treated cells leads to a strongly increased sensitivity to Bortezomib apoptotic cell death. Altogether our results suggest that the combination of Sunitinib and Bortezomib could be considered a promising treatment for endometrial carcinoma after failure of surgery and radiation. (C) 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Original languageEnglish
Pages (from-to)530-541
Number of pages12
JournalMolecular Oncology
Volume6
Issue number5
DOIs
Publication statusPublished - Oct 2012
Externally publishedYes

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