title: Sulforaphane inhibition of TPA-mediated PDCD4 downregulation contributes to suppression of c-Jun and induction of p21-dependent Nrf2 expression.
abstract: Programmed cell death 4 (PDCD4) is a bona fide tumor suppressor protein and plays a critical role in controlling the rate of protein synthesis. Here, we show that TPA selectively activated the S6K1 and ERK1/2 kinases, contributing to PDCD4 proteolysis and Pdcd4 mRNA degradation in HepG2 cells, respectively. In addition, we observed that sulforaphane suppression of TPA-induced S6K1 and ERK1/2 activation played a critical role in attenuating PDCD4 poly-ubiquitination and Pdcd4 mRNA downregulation. Moreover, we observed that silencing Pdcd4 led to not only an increased expression of c-Jun, but also a decreased expression of p21, the latter of which contributed to suppression of Keap1-dependent Nrf2 poly-ubiquitination. Finally, we demonstrate that the expression of PDCD4, p21 and Nrf2 is higher, but that of c-Jun is lower in normal human liver tissues, compared with hepatoma tissues. Collectively, our study illustrates that attenuating the rate of PDCD4 proteolysis and Pdcd4 mRNA degradation serves as a novel anti-inflammatory and cytoprotective mechanism of sulforaphane.
authors.affiliation: College of Pharmacy, Dongguk University, Goyang, Gyeonggi-do, 410-773, Republic of Korea.
authors.forename: Jong-Ho
authors.initials: JH
authors.lastname: Cho
authors.affiliation: College of Pharmacy, Dongguk University, Goyang, Gyeonggi-do, 410-773, Republic of Korea.
authors.forename: Young-Woo
authors.initials: YW
authors.lastname: Kim
authors.affiliation: Department of Pharmaceutical Science and Engineering, Seowon University, Cheongju, Chungbuk, 361-742, Republic of Korea.
authors.forename: Bu Young
authors.initials: BY
authors.lastname: Choi
authors.affiliation: College of Pharmacy, Dongguk University, Goyang, Gyeonggi-do, 410-773, Republic of Korea. Electronic address: keum03@dongguk.edu.
authors.forename: Young-Sam
authors.initials: YS
authors.lastname: Keum
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis*; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation; D016758:Genes, jun / Q000187:drug effects* / Q000502:physiology; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D013454:Sulfoxides; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors* / Q000494:pharmacology
chemical_list: D051017:Apoptosis Regulatory Proteins; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C114487:PDCD4 protein, human; D016601:RNA-Binding Proteins; D013454:Sulfoxides; C016766:sulforaphane; D013755:Tetradecanoylphorbol Acetate
keywords: ERK1/2; Nrf2; PDCD4; S6K1; Sulforaphane