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Int. J. Mol. Sci. 2019, 20(2), 270; https://doi.org/10.3390/ijms20020270

IL-1β Inflammatory Cytokine-Induced TP63 Isoform ∆NP63α Signaling Cascade Contributes to Cisplatin Resistance in Human Breast Cancer Cells

1
Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados del Instituto, Politécnico Nacional, Avenida Instituto Politécnico Nacional 2508, Ciudad de México 07360, Mexico
2
IDIX SA de CV, Sonterra 3035, Querétaro 76235, Mexico
*
Author to whom correspondence should be addressed.
Received: 16 November 2018 / Revised: 16 December 2018 / Accepted: 27 December 2018 / Published: 11 January 2019
(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells 2018)
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Abstract

The mechanisms behind the induction of malignancy and chemoresistance in breast cancer cells are still not completely understood. Inflammation is associated with the induction of malignancy in different types of cancer and is highlighted as an important factor for chemoresistance. In previous work, we demonstrated that the inflammatory cytokine interleukin 1β (IL-1β)-induced upregulation of genes was associated with chemoresistance in breast cancer cells. Here, we evaluated the participation and the expression profile of TP63 in the induction of resistance to cisplatin. By loss-of-function assays, we identified that IL-1β particularly upregulates the expression of the tumor protein 63 (TP63) isoform ΔNP63α, through the activation of the IL-1β/IL-1RI/β-catenin signaling pathway. Upregulation of ΔNP63α leads to an increase in the expression of the cell survival factors epidermal growth factor receptor (EGFR) and phosphatase 1D (Wip1), and a decrease in the DNA damage sensor, ataxia-telangiectasia mutated (ATM). The participation of these processes in the increase of resistance to cisplatin was confirmed by silencing TP63 expression or by inhibition of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) activity in the IL-1β/IL-1RI/β-catenin signaling pathway. These data reinforced the importance of an inflammatory environment in the induction of drug resistance in cancer cells and uncovered a molecular mechanism where the IL-1β signaling pathway potentiates the acquisition of cisplatin resistance in breast cancer cells. View Full-Text
Keywords: IL-1β; TP63 isoform ΔNP63α; short hairpin RNA (shRNA)-mediated knockdown; drug resistance acquisition; breast cancer IL-1β; TP63 isoform ΔNP63α; short hairpin RNA (shRNA)-mediated knockdown; drug resistance acquisition; breast cancer
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Mendoza-Rodríguez, M.G.; Ayala-Sumuano, J.T.; García-Morales, L.; Zamudio-Meza, H.; Pérez-Yepez, E.A.; Meza, I. IL-1β Inflammatory Cytokine-Induced TP63 Isoform ∆NP63α Signaling Cascade Contributes to Cisplatin Resistance in Human Breast Cancer Cells. Int. J. Mol. Sci. 2019, 20, 270.

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