title: Akt Cys-310-targeted inhibition by hydroxylated benzene derivatives is tightly linked to their immunosuppressive effects.
abstract: The hydroxylated benzene metabolite hydroquinone (HQ) is mainly generated from benzene, an important industrial chemical, and is also a common dietary component. Although numerous reports have addressed the tumorigenesis-inducing effects of HQ, few papers have explored its molecular regulatory mechanism in immunological responses. In this study we characterized Akt (protein kinase B)-targeted regulation by HQ and its derivatives, in suppressing inflammatory responses using cellular, molecular, biochemical, and immunopharmacological approaches. HQ down-regulated inflammatory responses such as NO production, surface levels of pattern recognition receptors, and cytokine gene expression with IC(50) values that ranged from 5 to 10 microm. HQ inhibition was mediated by blocking NF-kappaB activation via suppression of its translocation pathway, which is composed of Akt, I kappaB alpha kinase beta, and I kappaB alpha. Of the targets in this pathway, HQ directly targeted and bound to the sulfhydryl group of Cys-310 of Akt and sequentially interrupted the phosphorylation of both Thr-308 and Ser-473 by mediation of beta-mercaptoethanol, according to the liquid chromatography/mass spectroscopy analysis of the interaction of HQ with an Akt-derived peptide. Therefore, our data suggest that Akt and its target site Cys-310 can be considered as a prime molecular target of HQ-mediated immunosuppression and for novel anti-Akt-targeted immunosuppressive drugs.
authors.affiliation: School of Bioscience and Biotechnology and Institute of Bioscience and Biotechnology, Kangwon National University, Chuncheon 200-701.
authors.forename: Ji Yeon
authors.initials: JY
authors.lastname: Lee
authors.affiliation: School of Bioscience and Biotechnology and Institute of Bioscience and Biotechnology, Kangwon National University, Chuncheon 200-701.
authors.forename: Yong Gyu
authors.initials: YG
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Chung-Ang University, Seoul 156-756.
authors.forename: Jaehwi
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, Daejeon Regional Cancer Center, Cancer Research Institute, College of Medicine, Chungnam National University, Daejeon 310-010.
authors.forename: Keum-Jin
authors.initials: KJ
authors.lastname: Yang
authors.affiliation: School of Bioscience and Biotechnology and Institute of Bioscience and Biotechnology, Kangwon National University, Chuncheon 200-701.
authors.forename: Ae Ra
authors.initials: AR
authors.lastname: Kim
authors.affiliation: School of Bioscience and Biotechnology and Institute of Bioscience and Biotechnology, Kangwon National University, Chuncheon 200-701.
authors.forename: Joo Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Department of Anatomy and Neurobiology and Institute of Neurodegeneration and Neuroregeneration, College of Medicine, Hallym University, Chucheon 200-702.
authors.forename: Moo-Ho
authors.initials: MH
authors.lastname: Won
authors.affiliation: Department of Pharmacology, Daejeon Regional Cancer Center, Cancer Research Institute, College of Medicine, Chungnam National University, Daejeon 310-010.
authors.forename: Jongsun
authors.initials: J
authors.lastname: Park
authors.affiliation: Research Institute and Hospital, National Cancer Center, Goyang 410-769.
authors.forename: Byong Chul
authors.initials: BC
authors.lastname: Yoo
authors.affiliation: College of Pharmacy, Seoul National University, Seoul 151-741.
authors.forename: Sanghee
authors.initials: S
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Chonnam National University, Kwangju 500-757, Korea.
authors.forename: Won-Jea
authors.initials: WJ
authors.lastname: Cho
authors.affiliation: School of Bioscience and Biotechnology and Institute of Bioscience and Biotechnology, Kangwon National University, Chuncheon 200-701. Electronic address: jaecho@kangwon.ac.kr.
authors.forename: Jae Youl
authors.initials: JY
authors.lastname: Cho
mesh_terms: D000818:Animals; D001554:Benzene / Q000737:chemistry*; D002853:Chromatography, Liquid / Q000379:methods; D003545:Cysteine / Q000737:chemistry; D006873:Hydroquinones / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D008623:Mercaptoethanol / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018613:Microscopy, Confocal; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*
chemical_list: D006873:Hydroquinones; D007166:Immunosuppressive Agents; D008623:Mercaptoethanol; D051057:Proto-Oncogene Proteins c-akt; D001554:Benzene; D003545:Cysteine; C031927:hydroquinone