Nuclear receptors as novel regulators that modulate cancer radiosensitivity and normal tissue radiotoxicity.

Nuclear receptors (NRs) are a superfamily of transcription factors that are involved in various pathophysiological processes. The human genome contains 48 types of nuclear receptors, including steroid hormone receptors (e.g., estrogen receptor [ER] and vitamin D receptor [VDR]), nonsteroid hormone receptors (e.g. peroxisome proliferator-activated receptor [PPAR] and retinoic acid receptor [RAR]), and orphan nuclear receptors (e.g. neuron-derived clone 77 [Nur77] and testicular nuclear receptor 4 [TR4]) and certain nuclear receptors are specifically overexpressed in tumor cells or surrounding normal tissues. Radiotherapy is one of the main methods of tumor treatment, but radioresistance in tumors and radiotoxicity to normal tissues strongly affect radiotherapy efficacy. Accumulating evidence has indicated the critical role of nuclear receptor modulators (including agonists and antagonists) as promising radiosensitizers in radiotherapy through various mechanisms. In addition, several nuclear receptors and their agonists alleviate normal tissue toxicity during radiotherapy. Thus, nuclear receptors serve as novel targets for tumor radiosensitization and for protecting of normal tissues from radiation damage. This review summarizes the research progress of nuclear receptors and highlights a promising synergistic strategy in radiotherapy.