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Introduction
Radiotherapy is a powerful and common tool for the treatment of cancer. In fact, it is estimated that about one-half to two-thirds of cancer patients receive this type of therapy [1]. Although it has many advantages including local tumor control, a large proportion of patients experience radioresistance and cancer recurrence [2]. It is therefore necessary to determine the mechanisms underlying radioresistance and identify new pharmacological strategies to improve the efficiency of radiotherapy.
Several mechanisms of radioresistance have been suggested, involving cancer stem cells (CSCs), apoptosis, reactive oxygen species (ROS), and DNA damage repair. Currently, radiotherapy combined with targeted therapy has become the focus of studies on radiosensitization [3], so elucidating the signaling pathways involved in radioresistance is of primary importance.
Tumorigenesis involves a series of changes including the activation of oncogenes and inactivation of suppressor genes, and it is now well recognized that deregulation of Wnt signaling leads to cancer [4]. Given the tight association between Wnt signaling and cancer proliferation, apoptosis, and cancer stemness, Wnt signaling is thought associated with cancer radioresistance [5]. In this review, we discuss the close correlation between Wnt signaling and radioresistance and the mechanism by which Wnt signaling promotes radioresistance.
Mechanisms of radioresistance
Ionizing irradiation (IR) induces cancer cell death via a series of processes. First, it induces water radiolysis, thereby generating ROS. Then oxygen provides unpaired electrons for radicals within the DNA molecule, resulting in the stabilization of IR-induced DNA damage. Damaged DNA or excessive ROS activates apoptotic signaling pathways in cancer cells, leading to cell death [6] (Fig. 1). The success or failure of standard clinical radiation treatment is determined by the 4 R’s of radiobiology: repair of DNA damage, redistribution of the cell cycle, repopulation of tumors, and reoxygenation of hypoxic tumor areas [7]. Thus, according to the process of IR-induced cell death, we conclude that radioresistant cancer cells protect themselves from IR by reducing ROS-induced damage including hypoxia, activity of the anti-oxidant system, and ROS scavengers, thereby enhancing DNA repair and increasing DNA damage tolerance mainly by activating intracellular pro-survival and anti-apoptotic signaling pathways (Fig. 1).
Fig. 1.
[Image omitted. See PDF.]
Mechanisms of radioresistance. In response to IR, ROS is elevated and elevated ROS or IR then leads to DNA damage....