Abstract
The lung is one of the most sensitive tissues to ionizing radiation, thus, radiation-induced lung injury (RILI) stays a key dose-limiting factor of thoracic radiotherapy. However, there is still little progress in the effective treatment of RILI. Ras-related C3 botulinum toxin substrate1, Rac1, is a small guanosine triphosphatases involved in oxidative stress and apoptosis. Thus, Rac1 may be an important molecule that mediates radiation damage, inhibition of which may produce a protective effect on RILI. By establishing a mouse model of radiation-induced lung injury and orthotopic lung tumor-bearing mouse model, we detected the role of Rac1 inhibition in the protection of RILI and suppression of lung tumor. The results showed that ionizing radiation induces the nuclear translocation of Rac1, the latter then promotes nuclear translocation of P53 and prolongs the residence time of p53 in the nucleus, thereby promoting the transcription of Trp53inp1 which mediates p53-dependent apoptosis. Inhibition of Rac1 significantly reduce the apoptosis of normal lung epithelial cells, thereby effectively alleviating RILI. On the other hand, inhibition of Rac1 could also significantly inhibit the growth of lung tumor, increase the radiation sensitivity of tumor cells. These differential effects of Rac1 inhibition were related to the mutation and overexpression of Rac1 in tumor cells.
Highlights
The lung is one of the most sensitive tissues to ionizing radiation, radiation-induced lung injury (RILI) stays a key dose-limiting factor of thoracic radiotherapy and is an inevitable companion of thoracic radiotherapy [1]
Ras-related C3 botulinum toxin substrate1, Rac1, is small guanosine triphosphatases (GTPases) involved in oxidative stress [2,3,4], DNA damage [5, 6], and epithelial–mesenchymal transition (EMT) [7, 8], which are all important mechanisms of radiation-induced tissue damage
Radiation-induced lung injury was alleviated by Rac1 inhibition Compared with the Naive group, the alveolar septum of the IR group was significantly thickened and the alveolar infiltrated with inflammatory cells (Fig. 1A, B), the collagen fibers in the lung of the IR group was increased significantly from the first week and the proportion of collagen fibers gradually increased from the 3rd week to the 12th week (Fig. 1C, D), indicating that pulmonary inflammation and fibrosis was induced by IR
Summary
The lung is one of the most sensitive tissues to ionizing radiation, radiation-induced lung injury (RILI) stays a key dose-limiting factor of thoracic radiotherapy and is an inevitable companion of thoracic radiotherapy [1]. Radio-protectors should have minimal side effects, and above all, do not exert protective effects on tumor cells. Seeking such a radio-protective agent or molecular target that can mediate such a bidirectional effect has become the key to improving tumor radiotherapy. Rac may be an important molecule that mediates radiation damage, inhibition of which may produce a protective effect on RILI. Inhibition of Rac has the potential of protecting normal tissues from radiation-induced injury, and at the same time, inhibiting tumor growth and sensitizing tumor to radiation therapy, which makes it a promising ideal molecular target for the protection and treatment of radiation-induced lung injury caused by clinical radiotherapy
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