Brain tumor senescence might be mediated by downregulation of S-phase kinase-associated protein 2 via butylidenephthalide leading to decreased cell viability

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• 作者：Mao-Hsuan Huang (1)
  Shinn-Zong Lin (2) (3) (4) (5)
  Po-Cheng Lin (6)
  Tzyy-Wen Chiou (7)
  Yeu-Wei Harn (8)
  Li-Ing Ho (9)
  Tzu-Min Chan (10) (2)
  Chih-Wei Chou (11)
  Chang-Han Chuang (12)
  Hong-Lin Su (1) (15)
  Horng-Jyh Harn (13) (14)
  
• 关键词：S ; phase associated kinase protein 2 ; Glioblastoma multiform ; Butylidenephthalide ; Senescence
• 刊名：Tumor Biology
• 出版年：2014
• 出版时间：May 2014
• 年：2014
• 卷：35
• 期：5
• 页码：4875-4884
• 全文大小：
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• 作者单位：Mao-Hsuan Huang (1)
  Shinn-Zong Lin (2) (3) (4) (5)
  Po-Cheng Lin (6)
  Tzyy-Wen Chiou (7)
  Yeu-Wei Harn (8)
  Li-Ing Ho (9)
  Tzu-Min Chan (10) (2)
  Chih-Wei Chou (11)
  Chang-Han Chuang (12)
  Hong-Lin Su (1) (15)
  Horng-Jyh Harn (13) (14)
  
  1. Department of Life Sciences, Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Taiwan, Republic of China
  2. Center for Neuropsychiatry, China Medical University and Hospital, Taichung, Taiwan, Republic of China
  3. Department of Neurosurgery, China Medical University Beigan Hospital, Yunlin, Taiwan, Republic of China
  4. Department of Neurosurgery, Tainan Municipal An-Nan Hospital, China Medical University, Tainan, Taiwan, Republic of China
  5. Graduate Institute of Immunology, China Medical University, Taichung, Taiwan, Republic of China
  6. Department of Research and Development, Gwo Xi Stem Cell Applied Technology Co., Ltd., Hsinchu, Taiwan, Republic of China
  7. Department of Life Science and Graduate Institute of Biotechnology, National Dong-Hwa University, Hualien, Taiwan, Republic of China
  8. Double Specialty Program of Management and Technology, National Tsing Hua University, Hsinchu, Taiwan, Republic of China
  9. Department of Respiratory Therapy, Veterans General Hospital鈥擳aipei, Taipei, Taiwan, Republic of China
  10. Everfront Biotech Inc., New Taipei City, Taiwan, Republic of China
  11. Department of Cosmeceutics, China Medical University, Taichung, Taiwan, Republic of China
  12. Department of Orthopaedics, National Cheng Kung University Hospital, Tainan, Taiwan, Republic of China
  15. Department of Physical Therapy, China Medical University, Taichung, Taiwan, Republic of China
  13. Department of Pathology, China Medical University Hospital, No. 2, Yuh-Der Rd., Taichung, Taiwan, 40447, Republic of China
  14. Department of Medicine, China Medical University, Taichung, Taiwan, Republic of China
  
• ISSN：1423-0380

文摘

Developing an effective drug for treating human glioblastoma multiform (GBM) has been investigated persistently. A pure compound butylidenephthalide (BP), isolated from Angelica sinensis, has been shown the activities to arrest the growth and initiate apoptosis of GBM in our previous reports. In this study, we further demonstrated that BP treatment accelerates the cell senescence in a dose-dependent manner in vitro and in vivo. S-phase kinase-associated protein 2 (Skp2), a proto-oncogene, is generally upregulated in cancer. We found that it was downregulated in BP-treated GBM cells. The downregulation of Skp2 is parallel with increasing p16 and p21 expression which causes G0/G1 arrest and tumor cell senescence. We also found that restoring the Skp2 protein level by exogenous overexpression prevents the BP-induced cell senescence. Therefore, the linkage between cell senescence and Skp2 expression is strengthened. Promoter binding analysis further detailed that the BP-mediated SP1 reduction might involve in the Skp2 downregulation. In summary, these results emphasize that BP-triggered senescence in GBM cells is highly associated with its control on Skp2 regulation.