Increase in the radioresistance of normal skin fibroblasts but not tumor cells by mechanical injury.
The timing of radiation after mechanical injury such as in the case of surgery is considered a clinical challenge because radiation is assumed to impair wound healing. However, the physiological responses and underlying mechanisms of this healing impairment are still unclear. Here, we show that mechanical injury occurring before ionizing radiation decreases radiation-induced cell damage and increases cell repair in normal fibroblasts but not tumor cells in vitro and in vivo. At the molecular level, mechanical injury interrupts focal adhesion complexes and cell-cell cadherin interactions, transducing mechanical signals into intracellular chemical signals via activation of the phosphatidylinositol 3-kinase (PI3K), Akt, and glycogen synthase kinase 3 beta (GSK-3β) pathways. We show that subsequent nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and β-catenin strengthen the stemness, antioxidant capabilities, and DNA double-strand break repair abilities of fibroblasts, ultimately contributing to increased radioresistance. Our findings demonstrate that mechanical injury to normal fibroblasts enhances radioresistance and may therefore question conventional wisdom surrounding the timing of radiation after surgery.
Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing 400038, China.
Zelin
Z
Chen
Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing 400038, China.
Xin
X
Wang
Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing 400038, China.
Taotao
T
Jin
Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing 400038, China.
Yu
Y
Wang
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Christopher S
CS
Hong
Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing 400038, China.
Li
L
Tan
Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing 400038, China.
Tingyu
T
Dai
Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing 400038, China.
Liao
L
Wu
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Zhengping
Z
Zhuang
Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing 400038, China.
Chunmeng
C
Shi
D000818:Animals; D002448:Cell Adhesion / Q000528:radiation effects; D002460:Cell Line; D004260:DNA Repair / Q000528:radiation effects; D005347:Fibroblasts / Q000378:metabolism / Q000528:radiation effects*; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011839:Radiation, Ionizing; D015398:Signal Transduction / Q000528:radiation effects; D012867:Skin / Q000378:metabolism / Q000528:radiation effects*; D051176:beta Catenin / Q000378:metabolism
D051267:NF-E2-Related Factor 2; D051176:beta Catenin; D019869:Phosphatidylinositol 3-Kinases; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt