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.
Highlights
Radiation therapy is a staple cancer treatment approach that has significantly improved local disease control and the overall survival of cancer patients
HER1 has been reported to promote the activation of DNA-dependent protein kinase (DNA-PK), which plays an essential role in the non-homologous end joining repair (NHEJ)-mediated repair of DNA double-strand breaks (DSBs) [25,26]
As a standard of care, radiation therapy plays an important role in cancer therapy
Summary
The AKT signaling pathway plays a vital role in cell survival. Aberrant activation of this signaling cascade has been detected in various types of malignancies and is associated with tumorigenesis [54]. AKT phosphorylates/activates pro-survival protein XIAP (X-linked inhibitor of apoptosis protein), resulting in an increase of binding of XIAP to caspases 3, 7 and 9 and inhibition of these caspases, the activities of which are essential for apoptosis induction [63]. Another key pro‐survival pathway targeted by AKT is the mTOR signaling pathway. AKT is directly involved in the activation of the catalytic subunit of DNA-PK after radiation, promoting NHEJ-mediated DSB repair that increases cell survival [70] These studies establish a pro-survival role for AKT mediated signaling pathways in the response of cancer cells to radiation. In some cell‐based models, inhibition of PI3K/AKT has been shown to have little effect on radiosensitivity [29,80,81,82,83], suggesting an involvement of PI3K/AKT-independent mechanisms in the regulation of radiosensitivity
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