IL-1 beta Inflammatory Cytokine-Induced TP63 Isoform Delta NP63 alpha Signaling Cascade Contributes to Cisplatin Resistance in Human Breast Cancer Cells

摘要

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 1 beta (IL-1 beta)-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-1 beta particularly upregulates the expression of the tumor protein 63 (TP63) isoform Delta NP63 alpha, through the activation of the IL-1 beta/IL-1RI/beta-catenin signaling pathway. Upregulation of Delta NP63 alpha 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-1 beta/IL-1RI/beta-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-1 beta signaling pathway potentiates the acquisition of cisplatin resistance in breast cancer cells.