Version 1
: Received: 5 June 2023 / Approved: 5 June 2023 / Online: 5 June 2023 (16:38:38 CEST)
How to cite:
Wang, L.; Ni, J.; Ding, K.; Zhang, C.; Li, A.; Zhou, J. JAC4 Enhances Radiotherapy Effect of NSCLC and Reduces Normal Lung Injury Through Differential Regulation of JWA-mediated DNA Repair. Preprints2023, 2023060356. https://doi.org/10.20944/preprints202306.0356.v1
Wang, L.; Ni, J.; Ding, K.; Zhang, C.; Li, A.; Zhou, J. JAC4 Enhances Radiotherapy Effect of NSCLC and Reduces Normal Lung Injury Through Differential Regulation of JWA-mediated DNA Repair. Preprints 2023, 2023060356. https://doi.org/10.20944/preprints202306.0356.v1
Wang, L.; Ni, J.; Ding, K.; Zhang, C.; Li, A.; Zhou, J. JAC4 Enhances Radiotherapy Effect of NSCLC and Reduces Normal Lung Injury Through Differential Regulation of JWA-mediated DNA Repair. Preprints2023, 2023060356. https://doi.org/10.20944/preprints202306.0356.v1
APA Style
Wang, L., Ni, J., Ding, K., Zhang, C., Li, A., & Zhou, J. (2023). JAC4 Enhances Radiotherapy Effect of NSCLC and Reduces Normal Lung Injury Through Differential Regulation of JWA-mediated DNA Repair. Preprints. https://doi.org/10.20944/preprints202306.0356.v1
Chicago/Turabian Style
Wang, L., Aiping Li and Jianwei Zhou. 2023 "JAC4 Enhances Radiotherapy Effect of NSCLC and Reduces Normal Lung Injury Through Differential Regulation of JWA-mediated DNA Repair" Preprints. https://doi.org/10.20944/preprints202306.0356.v1
Abstract
More than 50% of patients with non-small cell lung cancer (NSCLC) are treated with radiotherapy (RT) during different phases of treatment. However, radiation pneu-monitis (RP) and resistance often lead to RT failure in NSCLC patients. JWA, a tumor suppressor gene, is known to enhance DNA damage in gastric cancer cells while protect normal cells from DNA damage induced by cisplatin. Recently, we have re-ported that JWA agonist compound 4 (JAC4) effectively protects intestinal epithelium from RT triggered damage in mice. However, the potential synergistic and attenuated effects of JAC4 in chest RT of lung cancer are not been illuminated. The aim of this study was to investigate the effects of JAC4 on the radiotoxicities of both NSCLC and normal lung tissue. CCK-8 and colony formation assays showed that JAC4 played a bidirectional role in radiation-treated SPCA-1 and BEAS-2B cells. Western blotting and immunofluorescence assays showed that JAC4 in combination with RT increased DNA damage and apoptosis in SPCA-1 cells, while the opposite effect was observed in BEAS-2B cells. Mechanistically, JAC4 inhibited homologous recombination repair (HR) and non-homologous end joining (NHEJ) in SPCA-1 cells, but not in normal cells. JAC4 increased antioxidant capacity, and reduced oxidative stress and inhibited nu-clear factor Kappa-B (NF-κB, P65) translocation to the nucleus in BEAS-2B cells. Im-portantly, the bidirectional roles of JAC4 on RT were reversed by siJWA in both SPCA-1 and BEAS-2B cells. Finally, the bidirectional effects of JAC4 in combination with RT were further validated in NSCLC xenograft model mice. In conclusion, JAC4 enhanced effect of RT on tumor growth while alleviated RP and lung injury. Our re-sults may provide new strategy for optimizing RT regimen for NSCLC.
Keywords
NSCLC; JAC4; DNA repair; radiotherapy; bidirectional effect
Subject
Medicine and Pharmacology, Pharmacology and Toxicology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
