title: 14-3-3β Depletion Drives a Senescence Program in Glioblastoma Cells Through the ERK/SKP2/p27 Pathway.
abstract: The induction of senescence in cancer cells has recently been implicated as a mechanism of tumor regression in response to various modes of stress. 14-3-3 proteins are conserved scaffolding molecules that are involved in various cellular functions. Among the seven isoforms, 14-3-3β is specifically expressed in astrocytoma in correlation with the malignancy grade. We investigated the possible role of 14-3-3β in the regulation of senescence induction in A172 glioblastoma cells. The knockdown of 14-3-3β by specific small interfering RNA resulted in a significant change in cellular phenotypes and an increase in cells staining positive for senescence-associated β-galactosidase. Western blotting of the 14-3-3β-depleted A172 cells revealed increased p27 expression and decreased SKP2 expression, while the expression of p53 and p21 was not altered. Subsequently, we demonstrated that ERK is a key modulator of SKP2/p27 axis activity in 14-3-3β-mediated senescence based on the following: (1) 14-3-3β knockdown decreased p-ERK levels; (2) treatment with U0126, an MEK inhibitor, completely reproduced the senescence morphology as well as the expression profiles of p27 and SKP2; and (3) the senescence phenotypes induced by 14-3-3β depletion were considerably recovered by constitutively active ERK expression. Our results indicate that 14-3-3β negatively regulates senescence in glioblastoma cells via the ERK/SKP2/p27 pathway. Furthermore, 14-3-3β depletion also resulted in senescence phenotypes in U87 glioblastoma cells, suggesting that 14-3-3β could be targeted to induce premature senescence as a therapeutic strategy against glioblastoma progression.
authors.affiliation: Department of Biochemistry, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea.|The Institute for Aging and Metabolic Diseases, College of Medicine, The Catholic University of Korea, Seoul, 06591, Republic of Korea.
authors.forename: Sung Bin
authors.initials: SB
authors.lastname: Seo
authors.affiliation: Tunneling Nanotube Research Center, Korea University, Seoul, 02841, Republic of Korea.
authors.forename: Je-Jung
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea.|The Institute for Aging and Metabolic Diseases, College of Medicine, The Catholic University of Korea, Seoul, 06591, Republic of Korea.
authors.forename: Hye Hyeon
authors.initials: HH
authors.lastname: Yun
authors.affiliation: Department of Biochemistry, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea.|The Institute for Aging and Metabolic Diseases, College of Medicine, The Catholic University of Korea, Seoul, 06591, Republic of Korea.
authors.forename: Chang-Nim
authors.initials: CN
authors.lastname: Im
authors.affiliation: Genome Editing Research Center, KRIBB, Daejeon, 34141, Republic of Korea.
authors.forename: Yong-Sam
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Genome Editing Research Center, KRIBB, Daejeon, 34141, Republic of Korea.
authors.forename: Jeong-Heon
authors.initials: JH
authors.lastname: Ko
authors.affiliation: Department of Biochemistry, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea. leejh@catholic.ac.kr.|The Institute for Aging and Metabolic Diseases, College of Medicine, The Catholic University of Korea, Seoul, 06591, Republic of Korea. leejh@catholic.ac.kr.
authors.forename: Jeong-Hwa
authors.initials: JH
authors.lastname: Lee
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000235:genetics*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism*
chemical_list: D048948:14-3-3 Proteins; D034741:RNA, Small Interfering; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27
keywords: 14-3-3β; ERK; Glioblastoma; Senescence