Radiation-induced signaling pathways that promote cancer cell survival (Review)

Abstract

Radiation therapy is a staple cancer treatment approach that has significantly improved local disease control and the overall survival of cancer patients. However, its efficacy is still limited by the development of radiation resistance and the presence of residual disease after therapy that leads to cancer recurrence. Radiation impedes cancer cell growth by inducing cytotoxicity, mainly caused by DNA damage. However, radiation can also simultaneously induce multiple pro-survival signaling pathways, such as those mediated by AKT, ERK and ATM/ATR, which can lead to suppression of apoptosis, induction of cell cycle arrest and/or initiation of DNA repair. These signaling pathways act conjointly to reduce the magnitude of radiation-induced cytotoxicity and promote the development of radioresistance in cancer cells. Thus, targeting these pro-survival pathways has great potential for the radiosensitization of cancer cells. In the present review, we summarize the current literature on how these radiation-activated signaling pathways promote cancer cell survival.

Pharmacological targeting of the ephrin receptor kinase signalling by GLPG1790 in vitro and in vivo reverts oncophenotype, induces myogenic differentiation and radiosensitizes embryonal rhabdomyosarcoma cells

“…Combined siRNA knockdown of both EPH-A2 and EPH-B2 genes, herein, shown and known [18] to be overexpressed in ERMS tumours, replicated many of the phenotypic effects observed in ERMS cells after drug exposure, confirming that GLPG1790 activity is mediated by the efficient impairment of EPH activity [21]. Finally, our data underline the role of GLPG1790 exposure in potentiating the effects of radiotherapy, which usually works by inducing DSBs as well as by inhibiting the non-homologous end joining (NHEJ) and the homologous recombination (HR) DNA repair pathways in exposed tumour cells [47]. Indeed, GLPG1790 enhanced radiosensitivity of ERMS cell lines, as demonstrated by the clonogenic survival reduction of more Fig.…”

“…Even if the relationship between EPH/Ephrin signalling, DSB repair machinery and response to RT is still largely unknown; a correlation between EPH overexpression and the acquisition of a radioresistant phenotype has been reported in other solid tumours [34,35,49,50]. Here, we showed that GLPG1790 abrogates the RT-induced ATM and DNA-PKcs phosphorylation, whose activation is linked to the HR and NHEJ pathways, respectively [47]. Augmentation of radiation response by GLPG1790 treatment was also confirmed by our preliminary in vivo experiments, in which the combination therapy with GLPG1790 and fractionated radiation was significantly more effective than the drug or the RT alone in reducing tumour masses.…”

Phosphatidylinositol 3-kinase/Akt signaling as a key mediator of tumor cell responsiveness to radiation

“…This argument is also applicable to those studies, in which inhibition of Akt and increased apoptosis were observed after targeting of upstream regulators of Akt, such as EGFR [131]. Given that radiosensitization can be achieved by enhancing different modes of cell death , such as mitotic catastrophe, autophagy, senescence [132][133][134] and apoptosis, the specific role of apoptosis as a mechanism of radiosensitization in solid tumors in general, and especially following Akt targeting, is questionable and requires further investigation.…”

Growth factors and kinases in glioblastoma growth

“…Currently, there are several drugs such as lithium chloride, valproic acid, olanzapine, and cimetidine, among others, which are used to treat other diseases but have shown an inhibitory effect on GSK3β [134] . It has been reported that glioblastomas have defects in apoptotic pathways including Bcl-2 [140,141] , which is also a downstream target of the PI3K/Akt pathway [142] . Cancer cells are protected from apoptosis by the up-regulation of various anti-apoptotic molecules such as Bcl-2, which has been reported to be overexpressed in glioblastoma [143,144] .…”