Research Paper Volume 12, Issue 18 pp 18501—18521

D-galactose induces senescence of glioblastoma cells through YAP-CDK6 pathway

Xingxing Xu1,2,3, *, , Xiya Shen1,2,3, *, , Wenjin Feng4, *, , Danlu Yang1,2,3, , Lingting Jin1,2,3, , Jiaojiao Wang1,2,3, , Mianxian Wang1,2,3, , Zhang Ting6, , Feng Xue1, , Jingjing Zhang1,2,3, , Chaobo Meng1, , Roumeng Chen1, , Xinru Zheng1, , Leilei Du1, , Lina Xuan1, , Ying Wang5, , Tian Xie2,3, , Zhihui Huang1,2,3, ,

  • 1 School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China
  • 2 Key Laboratory of Elemene Anti-Cancer Medicine of Zhejiang Province and Holistic Integrative Pharmacy Institutes, and Department of Neurosurgery of Affiliated Hospital, Hangzhou Normal University, Hangzhou 311121, China
  • 3 Department of Orthopedics (Spine Surgery), The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, Zhejiang, China
  • 4 Zhejiang Sinogen Medical Equipment Co., Ltd, Wenzhou, 325000, Zhejiang, China
  • 5 Department of Transfusion Medicine, Zhejiang Provincial People’s Hospital of Hangzhou Medical College, Hangzhou 310053, China
  • 6 Department of Neurobiology, Key Laboratory of Medical Neurobiology, Ministry of Health of China, School of Medicine, Zhejiang University, Hangzhou,310058, China
* Equal contribution

Received: October 27, 2019       Accepted: June 29, 2020       Published: September 29, 2020      

https://doi.org/10.18632/aging.103819
How to Cite

Copyright: © 2020 Xu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Treatment of glioblastoma using radiotherapy and chemotherapy has various outcomes, key among them being cellular senescence. However, the molecular mechanisms of this process remain unclear. In the present study, we tested the ability of D-galactose (D-gal), a reducing sugar, to induce senescence in glioblastoma cells. Following pretreatment with D-gal, glioblastoma cell lines (C6 and U87MG) showed typical characteristics of senescence. These included the reduced cell proliferation, hypertrophic morphology, increased senescence-associated β-galactosidase activity, downregulation of Lamin B1, and upregulation of several senescence-associated genes such as p16, p53, and NF-κB. Furthermore, our results showed that D-gal was more suitable than etoposide (a DNA-damage drug) in inducing senescence of glioblastoma cells. Mechanistically, D-gal inactivated the YAP-CDK6 signaling pathway, while overexpression of YAP or CDK6 could restore D-gal-induced senescence of C6 cells. Finally, metformin, an anti-aging agent, activated the YAP-CDK6 pathway and suppressed D-gal-induced senescence of C6 cells. Taken together, these findings established a new model for analyzing senescence in glioblastoma cells, which occurred through the YAP-CDK6 pathway. This is expected to provide a basis for development of novel therapies for the treatment of glioblastoma.

Abbreviations

D-gal: D-galactose; GBM: glioblastoma; YAP: yes-associated protein; CDK6: cyclin-dependent kinase 6; SASP: senescence-associated secretory phenotype; qPCR: quantitative real-time PCR.