14-3-3β Depletion Drives a Senescence Program in Glioblastoma Cells Through the ERK/SKP2/p27 Pathway

• Published in: Molecular neurobiology Vol. 55; no. 2; pp. 1259 - 1270
• Main Authors: Seo, Sung Bin, Lee, Je-Jung, Yun, Hye Hyeon, Im, Chang-Nim, Kim, Yong-Sam, Ko, Jeong-Heon, Lee, Jeong-Hwa
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.02.2018; Springer Nature B.V
• Subjects: 14-3-3 protein; 14-3-3 Proteins - genetics; 14-3-3 Proteins - metabolism; Astrocytoma; Biomedical and Life Sciences; Biomedicine; Brain; Brain cancer; Cancer; Cell Biology; Cell Cycle - genetics; Cell Line, Tumor; Cells; Cellular Senescence - genetics; Cyclin-Dependent Kinase Inhibitor p27 - metabolism; Depletion; Extracellular signal-regulated kinase; Glioblastoma; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma - pathology; Glioblastoma cells; Humans; Isoforms; Malignancy; MAP Kinase Signaling System - genetics; MEK inhibitors; Neurobiology; Neurology; Neurosciences; p53 Protein; Proteins; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; S-Phase Kinase-Associated Proteins - metabolism; Senescence; siRNA; Tumors; Western blotting; β-Galactosidase; Senescence; 14-3-3β; Glioblastoma; ERK
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-017-0407-8

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.