The p53 Protein Family in the Response of Tumor Cells to Ionizing Radiation: Problem Development

Kuchur, Oleg A.; Kuzmina, D.O.; Dukhinova, Marina; Штиль, А. А.

doi:10.32607/actanaturae.11247

Cited by 7 publications

(4 citation statements)

References 140 publications

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“…The overexpression of the cell-cycle-related protein p21Cip1/Waf1 renders cancer cells resistant to radiation [ 39 , 40 ]. P21 transcription is regulated by p53, the key transcription factor of the DDR pathway, which works together with p53-family proteins during the cell response to IR [ 41 ]. Alterations in the p53 pathway have a role in the radioresistance of pediatric tumors [ 42 , 43 , 44 ], endometrial cancer [ 45 ], head and neck cancer [ 46 ], rhabdomyosarcoma [ 47 ], and oral squamous cell carcinoma [ 48 ].…”

Section: Molecular and Cellular Features Associated With Radioresistancementioning

confidence: 99%

Biological Mechanisms to Reduce Radioresistance and Increase the Efficacy of Radiotherapy: State of the Art

Busato

Khouzai

Mognato

2022

IJMS

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Cancer treatment with ionizing radiation (IR) is a well-established and effective clinical method to fight different types of tumors and is a palliative treatment to cure metastatic stages. Approximately half of all cancer patients undergo radiotherapy (RT) according to clinical protocols that employ two types of ionizing radiation: sparsely IR (i.e., X-rays) and densely IR (i.e., protons). Most cancer cells irradiated with therapeutic doses exhibit radio-induced cytotoxicity in terms of cell proliferation arrest and cell death by apoptosis. Nevertheless, despite the more tailored advances in RT protocols in the last few years, several tumors show a relatively high percentage of RT failure and tumor relapse due to their radioresistance. To counteract this extremely complex phenomenon and improve clinical protocols, several factors associated with radioresistance, of both a molecular and cellular nature, must be considered. Tumor genetics/epigenetics, tumor microenvironment, tumor metabolism, and the presence of non-malignant cells (i.e., fibroblast-associated cancer cells, macrophage-associated cancer cells, tumor-infiltrating lymphocytes, endothelial cells, cancer stem cells) are the main factors important in determining the tumor response to IR. Here, we attempt to provide an overview of how such factors can be taken advantage of in clinical strategies targeting radioresistant tumors.

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Section: Molecular and Cellular Features Associated With Radioresistancementioning

confidence: 99%

Biological Mechanisms to Reduce Radioresistance and Increase the Efficacy of Radiotherapy: State of the Art

Busato

Khouzai

Mognato

2022

IJMS

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“…One of the key tumor suppressors that modulates the activity of dozens of cascades responsible for normal cell development, apoptotic and repair processes is the p53 protein [4,5]. This also leads to the problem -tissue malignancy is often accompanied by the acquisition of p53 driver mutations, as a result of which tumor suppressor functions are lost, which entails uncontrolled division, weakening of repair processes, and the formation of chemo-or radioresistance, for example, in breast and lung tumors [6][7][8]. Changes in p53 functions can be caused not only by mutations in the TP53 gene, but also epigenetically (phosphorylation by Cdc2, JNK1, protein kinase C) [9], as well as mutations of the TP53 regulators -TP53BP1, Chek2, ATM, Usp28, which leads to a weakening of the control of cellular division [10].…”

Section: Introductionmentioning

confidence: 99%

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

Kuchur,

Pogodaeva,

Shcherbakova

et al. 2024

Preprint

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The search for relevant molecular targets is one of the main tasks of modern tumor chemotherapy. To successfully achieve this, it is necessary to have the most complete understanding of the functioning of the cell's transcriptional apparatus, particularly related to proliferation. The p53 protein plays an important role in regulating processes such as apoptosis, repair, and cell division, and the loss of its functionality often accompanies various types of tumors and contributes to the development of chemoresistance. Additionally, the proliferative activity of tumor cells is closely related to the metabolism of transition metals. For example, the metallochaperone Atox1, a copper transporter protein, acts as a transcription activator for cyclin D1, promoting progression through the G1/S phase of the cell cycle. On the other hand, p53 suppresses cyclin D1 at the transcriptional level, thereby these proteins have divergent effects on cell cycle progression. However, the contribution of the interaction between these proteins to cell survival is poorly understood. This work demonstrates that there not only exists a positive feedback loop between Atox1 and cyclin D1, but also that the activity of this loop depends on the status of the TP53 gene. Upon inactivation of TP53 in A549 and HepG2 cell lines, the expression of ATOX1 and CCND1 genes is enhanced, and their suppression in these cells leads to pronounced apoptosis. This fundamental observation may be useful in selecting more precise interventions for combined therapy of p53-negative tumors.

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“…One of the most obvious markers, whose history began more than 40 years ago, is the oncosuppressor p53. This protein is a crucial regulator of tumor survival and death, an inducer of apoptosis, reparative processes, and also plays an important role in cell response to ROS damage [1][2][3][4]. Furthermore, the balance of redox reactions in the cell is closely linked to the regulation of intracellular homeostasis of transition metals such as zinc (Zn), iron (Fe), and copper (Cu) [5][6][7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

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

Tsymbal,

Refeld,

Zatsepin

et al. 2023

PLoS ONE

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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.

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The p53 Protein Family in the Response of Tumor Cells to Ionizing Radiation: Problem Development

Cited by 7 publications

References 140 publications

Biological Mechanisms to Reduce Radioresistance and Increase the Efficacy of Radiotherapy: State of the Art

Biological Mechanisms to Reduce Radioresistance and Increase the Efficacy of Radiotherapy: State of the Art

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

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

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