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

Molecular Neurobiology volume 55, pages 1259–1270 (2018)Cite this article

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.

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Acknowledgements

This research was supported by the Basic Science Research Programs through the National Research Foundation of Korea (NRF), funded by the Minister of Education, Science and Technology (2012R1A5A2047939), and the National Research Council of Science and Technology (CAP-15-03-KRIBB).

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  1. Department of Biochemistry, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea

    Sung Bin Seo, Hye Hyeon Yun, Chang-Nim Im & Jeong-Hwa Lee

  2. The Institute for Aging and Metabolic Diseases, College of Medicine, The Catholic University of Korea, Seoul, 06591, Republic of Korea

    Sung Bin Seo, Hye Hyeon Yun, Chang-Nim Im & Jeong-Hwa Lee

  3. Tunneling Nanotube Research Center, Korea University, Seoul, 02841, Republic of Korea

    Je-Jung Lee

  4. Genome Editing Research Center, KRIBB, Daejeon, 34141, Republic of Korea

    Yong-Sam Kim & Jeong-Heon Ko

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  1. Sung Bin Seo
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Seo, S.B., Lee, JJ., Yun, H.H. et al. 14-3-3β Depletion Drives a Senescence Program in Glioblastoma Cells Through the ERK/SKP2/p27 Pathway. Mol Neurobiol 55, 1259–1270 (2018). https://doi.org/10.1007/s12035-017-0407-8

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Keywords

  • 14-3-3β
  • Glioblastoma
  • Senescence
  • ERK