The p53 protein is a suppressor of Atox1 copper chaperon in tumor cells under genotoxic effects

Abstract

The p53 protein is crucial for regulating cell survival and apoptosis in response to DNA damage. However, its influence on therapy effectiveness is controversial: when DNA damage is high p53 directs cells toward apoptosis, while under moderate genotoxic stress it saves the cells from death and promote DNA repair. Furthermore, these processes are influenced by the metabolism of transition metals, particularly copper since they serve as cofactors for critical enzymes. The metallochaperone Atox1 is under intensive study in this context because it serves as transcription factor allegedly mediating described effects of copper. Investigating the interaction between p53 and Atox1 could provide insights into tumor cell survival and potential therapeutic applications in oncology. This study explores the relationship between p53 and Atox1 in HCT116 and A549 cell lines with wild type and knockout TP53. The study found an inverse correlation between Atox1 and p53 at the transcriptional and translational levels in response to genotoxic stress. Atox1 expression decreased with increased p53 activity, while cells with inactive p53 had significantly higher levels of Atox1. Suppression of both genes increased apoptosis, while suppression of the ATOX1 gene prevented apoptosis even under the treatment with chemotherapeutic drugs. The findings suggest that Atox1 may act as one of key elements in promotion of cell cycle under DNA-damaging conditions, while p53 works as an antagonist by inhibiting Atox1. Understanding of this relationship could help identify potential targets in cell signaling pathways to enhance the effectiveness of combined antitumor therapy, especially in tumors with mutant or inactive p53.

Atox1-Cyclin D1 Loop Activity is Critical for Survival of Tumor Cells with Inactivated TP53

“…At the same time, the coregulation of ATOX1 and CCND1 was reproduced by different methods of TP53 inactivation in the lung and liver tumor cells, and the responses to chemotherapeutic effects in different experimental models were comparable. Previously, in the A549 and HCT116 lines, we have already shown the dependence of the Atox1 level on the status and activity of p53 and p21 [37]. Experiments with siRNA-mediated inactivation of TP53 on A549 are not repeated in this study.…”

“…The regulation of Atox1 and the intensity of copper ions transportation into the nucleus depend on p53: in MEF cells with knockdown of the TP53 gene, the functions of Atox1 and Atox1-mediated regulation of CCND1 are reduced [35, 36]. On the other hand, our previous study shows that in cells of epithelial origin, inactivation (knockout or knockdown) of TP53 induces ATOX1 and increases the amount of its product [37], which may indicate tissue-dependent regulation.…”

Atox1-cyclin D1 loop activity is critical for survival of tumor cells with inactivated TP53

“…At the same time, the coregulation of ATOX1 and CCND1 was reproduced by different methods of TP53 inactivation in the lung and liver tumor cells, and the responses to chemotherapeutic effects in different experimental models were comparable, which tells about more fundamental interconnection between TP53 , ATOX1 , and CCND1 that may be incorporated into the sophisticated signaling network of cell cycle regulation (see discussion below). Previously, in the A549 and HCT116 lines, we have already shown the dependence of the Atox1 level on the status and activity of p53 and p21 [ 38 ]. The relationships identified at the mRNA level are confirmed by studying the corresponding proteins: suppression of ATOX1 expression entails a decrease in cyclin D1, and vice versa.…”

“…The regulation of Atox1 and the intensity of copper ions transportation into the nucleus depend on p53: in MEF cells with knockdown of the TP53 gene, the functions of Atox1 and Atox1-mediated regulation of CCND1 are reduced [ 36 , 37 ]. On the other hand, our previous study shows that in cells of epithelial origin, inactivation (knockout or knockdown) of TP53 induces ATOX1 and increases the amount of its product [ 38 ], which may indicate tissue-dependent regulation.…”

Atox1 regulates macrophage polarization in intestinal inflammation via ROS-NLRP3 inflammasome pathway

“…Atox1 provides copper to P-type ATPases that transport copper, which are essential for the proper functioning of numerous cellular processes, including redox homeostasis, energy production, and cell signaling [ 11 ]. Atox1 is also a crucial regulator of cell proliferation, cell cycle, metastasis, and DNA repair and represents a potential target in cancer therapy including colon cancer [ 12 – 14 ]. Moreover, in a study, Atox1 expression was found to be higher in active ulcerative colitis samples, was negatively correlated with CD8 + T cell infiltration, and showed excellent diagnostic value for ulcerative colitis [ 15 ].…”