Investigação da relação entre APE1 e NF-κB em modelos de câncer de mama

Abstract

Breast cancer is the most common form of cancer among women worldwide. Late detection of this disease is associated with increased mortality, primarily due to the occurrence of metastases. In this context, inhibiting the enzyme AP-endonuclease 1 (APE1) has been proposed as a promising therapeutic target. APE1 plays a central role in DNA repair and regulates transcription factors such as p65 of the NF-κB pathway, known to contribute to an aggressive phenotype in breast cancer cells. Thus, this study aimed to investigate the relationship between APE1 and NF-κB in cellular processes such as viability, proliferation, cell death, migration and invasion, cell cycle, and redox profile in breast cancer cells. The results indicated a correlation between APE1 and NF-κB in breast cancer patients based on data from the TCGA database. The combined treatment with the APE1 and NF-κB inhibitors also effectively reduced tumor cell viability and colony formation potential. Individually, the inhibitors induced cell death and cell cycle arrest in the MDA-MB-231 cell line, while the combined treatment led to cell death through late apoptosis and necrosis in both tested cell lines. Regarding cell migration, individual inhibitors significantly reduced migration in both cell lines, with the combined treatment being particularly effective in the MCF-7 cell line. In terms of cell invasion, individual inhibitors reduced invasion potential in the MDA-MB-231 cell line, but the combination of inhibitors showed no additional effect. Conversely, in the MCF-7 cell line, the combination was more effective, reducing invasion and modulating the expression of genes related to epithelial-mesenchymal transition (EMT), which can impact the invasive and metastatic characteristics of tumor cells. The results also demonstrated that the APX2009 inhibitor does not alter the expression of APE1 and NF-κB/p65 in either cell line but reduces the expression of MMP9 in MCF-7 cells. Furthermore, it was observed that the redox activity of APE1 is related to total reactive oxygen species (ROS) levels in breast cancer, and the NF-κB pathway may mediate this relationship. In conclusion, the interaction between APE1 and NF-κB influences fundamental processes in breast cancer, such as viability, clonogenicity, cell death, cell cycle, migration, and invasion. The synergistic effects observed with the combined treatment of APX2009 and BMS-345541, particularly in the MCF-7 cell line, highlight the potential of these proteins as therapeutic targets. Additionally, the role of APE1 in controlling oxidative stress opens new perspectives for developing personalized strategies for breast cancer treatment.