Cell Signaling Pathways That Promote Radioresistance of Cancer Cells.

Michel M Ouellette,Ying Yan,Sumin Zhou

doi:10.3390/diagnostics12030656

Michel M Ouellette, Ying Yan + Show 1 more

Open Access

https://doi.org/10.3390/diagnostics12030656

Copy DOI

Journal: Diagnostics	Publication Date: Mar 8, 2022
Citations: 27	License type: CC BY 4.0

Affiliation: University of Nebraska Medical Center

Abstract

Radiation therapy (RT) is a standard treatment for solid tumors and about 50% of patients with cancer, including pediatric cancer, receive RT. While RT has significantly improved the overall survival and quality of life of cancer patients, its efficacy has still been markedly limited by radioresistance in a significant number of cancer patients (intrinsic or acquired), resulting in failure of the RT control of the disease. Radiation eradicates cancer cells mainly by causing DNA damage. However, radiation also concomitantly activates multiple prosurvival signaling pathways, which include those mediated by ATM, ATR, AKT, ERK, and NF-κB that promote DNA damage checkpoint activation/DNA repair, autophagy induction, and/or inhibition of apoptosis. Furthermore, emerging data support the role of YAP signaling in promoting the intrinsic radioresistance of cancer cells, which occurs through its activation of the transcription of many essential genes that support cell survival, DNA repair, proliferation, and the stemness of cancer stem cells. Together, these signaling pathways protect cancer cells by reducing the magnitude of radiation-induced cytotoxicity and promoting radioresistance. Thus, targeting these prosurvival signaling pathways could potentially improve the radiosensitivity of cancer cells. In this review, we summarize the contribution of these pathways to the radioresistance of cancer cells.

Highlights

Radiation therapy (RT) is routinely used for cancer treatment, and more than fifty percent of patients with cancer, including pediatric cancer, receive RT as part of their treatment [1]
The current literature indicates that ionizing radiation (IR) can activate numerous cellular signaling pathways which lead to the induction of senescence, apoptosis, autophagy, and/or cell cycle checkpoint activation and DNA repair (Figure 1) [1,10–15]
These studies show that inhibition of PI3K/AKT signaling either by chemical or biological inhibitors can enhance the radiosensitivity in some cancer cell types, which is accompanied by diminished DNA repair and increased apoptosis induction [73–75,113,122,123]

Summary

Introduction

Radiation therapy (RT) is routinely used for cancer treatment, and more than fifty percent of patients with cancer, including pediatric cancer, receive RT as part of their treatment [1]. The current literature indicates that ionizing radiation (IR) can activate numerous cellular signaling pathways which lead to the induction of senescence, apoptosis, autophagy (leading to cell death or survival), and/or cell cycle checkpoint activation and DNA repair (Figure 1) [1,10–15]. ATM (Ataxia Telangiesctasia Mutated) and ATR (Ataxia Telangiectasia and Rad3related) kinase-mediated signaling pathways play essential roles in the activation of cell cycle checkpoint response and DNA repair following radiation-induced DNA damage (Figure 2) [21,22]. Activation of the three pathways by radiation results in the inhibition of Cdk activities leading to cell cycle arrest to allow time for DNA repair and cell survival [12]

DNA Repair Pathways

IR-Activated ERK1/2 Signaling Pathway

The PI3K/AKT Signaling Promotes Cell Survival in

NF-κB Signaling Pathway Promotes Radioresistance

YAP Signaling Pathway Promotes Radioresistance of Tumors

Findings

Conclusions