한빛사논문
- 조회488
Jung-Jin Park1,3, Kwangseok Oh1,3, Gun-Wu Lee1,3, Geul Bang2,3, Jin-Hee Park1, Han-Byeol Kim1, Jin Young Kim2, Eun-Young Shin1 and Eung-Gook Kim1
1Department of Biochemistry, Chungbuk National University College of Medicine, Cheongju 28644, Korea.
2Research Center for Bioconvergence Analysis, Korea Basic Science Institute, Ochang 28119, Korea.
3These authors contributed equally: Jung-Jin Park, Kwangseok Oh, Gun-Wu Lee, Geul Bang.
Corresponding authors : Correspondence to Eun-Young Shin or Eung-Gook Kim.
Abstract
Senescence, a hallmark of aging, is a factor in age-related diseases (ARDs). Therefore, targeting senescence is widely regarded as a practicable method for modulating the effects of aging and ARDs. Here, we report the identification of regorafenib, an inhibitor of multiple receptor tyrosine kinases, as a senescence-attenuating drug. We identified regorafenib by screening an FDA-approved drug library. Treatment with regorafenib at a sublethal dose resulted in effective attenuation of the phenotypes of βPIX knockdown- and doxorubicin-induced senescence and replicative senescence in IMR-90 cells; cell cycle arrest, and increased SA-β-Gal staining and senescence-associated secretory phenotypes, particularly increasing the secretion of interleukin 6 (IL-6) and IL-8. Consistent with this result, slower progression of βPIX depletion-induced senescence was observed in the lungs of mice after treatment with regorafenib. Mechanistically, the results of proteomics analysis in diverse types of senescence indicated that growth differentiation factor 15 and plasminogen activator inhibitor-1 are shared targets of regorafenib. Analysis of arrays for phospho-receptors and kinases identified several receptor tyrosine kinases, including platelet-derived growth factor receptor α and discoidin domain receptor 2, as additional targets of regorafenib and revealed AKT/mTOR, ERK/RSK, and JAK/STAT3 signaling as the major effector pathways. Finally, treatment with regorafenib resulted in attenuation of senescence and amelioration of porcine pancreatic elastase-induced emphysema in mice. Based on these results, regorafenib can be defined as a novel senomorphic drug, suggesting its therapeutic potential in pulmonary emphysema.
논문정보
- Research article
- 2023년 04월 (BRIC 등록일 2023-06-14)
- 국내 연구진
- 의약학 > 분자세포의학
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