title: The underlying mechanism of proinflammatory NF-κB activation by the mTORC2/Akt/IKKα pathway during skin aging.
abstract: Mammalian target of rapamycin complex 2 (mTORC2), one of two different enzymatic complexes of mTOR, regulates a diverse set of substrates including Akt. mTOR pathway is one of well-known mediators of aging process, however, its role in skin aging has not been determined. Skin aging can be induced by physical age and ultraviolet (UV) irradiation which are intrinsic and extrinsic factors, respectively. Here, we report increased mTORC2 pathway in intrinsic and photo-induced skin aging, which is implicated in the activation of nuclear factor-κB (NF-κB). UVB-irradiated or aged mice skin revealed that mTORC2 activity and its component, rictor were significantly upregulated which in turn increased Akt activation and Akt-dependent IκB kinase α (IKKα) phosphorylation at Thr23 in vivo. We also confirmed that UVB induced the mTORC2/Akt/IKKα signaling pathway with HaCaT human normal keratinocytes. The increased mTORC2 signaling pathway during skin aging were associated to NF-κB activation. Suppression of mTORC2 activity by the treatment of a mTOR small inhibitor or knockdown of RICTOR partially rescued UVB-induced NF-κB activation through the downregulation of Akt/IKKα activity. Our data demonstrated the upregulation of mTORC2 pathway in intrinsic and photo-induced skin aging and its role in IKKα/NF-κB activation. These data not only expanded the functions of mTOR to skin aging but also revealed the therapeutic potential of inhibiting mTORC2 in ameliorating both intrinsic skin aging and photoaging.
authors.affiliation: Molecular Inflammation Research Center for Aging Intervention, College of Pharmacy, Pusan National University, Busan, Korea.
authors.forename: Yeon Ja
authors.initials: YJ
authors.lastname: Choi
authors.affiliation: Molecular Inflammation Research Center for Aging Intervention, College of Pharmacy, Pusan National University, Busan, Korea.
authors.forename: Kyoung Mi
authors.initials: KM
authors.lastname: Moon
authors.affiliation: Molecular Inflammation Research Center for Aging Intervention, College of Pharmacy, Pusan National University, Busan, Korea.
authors.forename: Ki Wung
authors.initials: KW
authors.lastname: Chung
authors.affiliation: Molecular Inflammation Research Center for Aging Intervention, College of Pharmacy, Pusan National University, Busan, Korea.
authors.forename: Ji Won
authors.initials: JW
authors.lastname: Jeong
authors.affiliation: Molecular Inflammation Research Center for Aging Intervention, College of Pharmacy, Pusan National University, Busan, Korea.|Department of Predictive Toxicology, Korea Institute of Toxicology, Daejeon, Korea.|Human and Environmental Toxicology, School of Engineering, University of Science and Technology, Daejeon, Korea.
authors.forename: Daeui
authors.initials: D
authors.lastname: Park
authors.affiliation: Molecular Inflammation Research Center for Aging Intervention, College of Pharmacy, Pusan National University, Busan, Korea.
authors.forename: Dae Hyun
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Department of Physiology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Byung Pal
authors.initials: BP
authors.lastname: Yu
authors.affiliation: Molecular Inflammation Research Center for Aging Intervention, College of Pharmacy, Pusan National University, Busan, Korea.
authors.forename: Hae Young
authors.initials: HY
authors.lastname: Chung
mesh_terms: D000818:Animals; D002460:Cell Line; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism / Q000528:radiation effects; D008297:Male; D000076225:Mechanistic Target of Rapamycin Complex 2 / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation / Q000528:radiation effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000528:radiation effects; D012867:Skin / Q000378:metabolism / Q000528:radiation effects; D015595:Skin Aging; D014466:Ultraviolet Rays
chemical_list: D016328:NF-kappa B; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D051550:I-kappa B Kinase
keywords: Gerotarget; NF-κB; UV; mTORC2; skin aging