Tumor Biology

, Volume 35, Issue 5, pp 4875–4884 | Cite as

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

  • Mao-Hsuan Huang
  • Shinn-Zong Lin
  • Po-Cheng Lin
  • Tzyy-Wen Chiou
  • Yeu-Wei Harn
  • Li-Ing Ho
  • Tzu-Min Chan
  • Chih-Wei Chou
  • Chang-Han Chuang
  • Hong-Lin Su
  • Horng-Jyh HarnEmail author
Research Article


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.


S-phase associated kinase protein 2 Glioblastoma multiform Butylidenephthalide Senescence 





Glioblastoma multiform


S-phase kinase-associated protein 2



This work was supported by National Science Council of the Republic of China (NSC 102-2320-B-039-011), Taiwan Department of Health Clinical Trial and Research Center of Excellence (DOH102-TD-B-111-004); Aim for the Top University Plan of the National Chiao Tung University and Ministry of Education, Cancer Research Center of Excellence (Taiwan) and Ministry of Economic Affairs (102-EC-17-A-19-I1-0051).

Conflicts of interest



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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • 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
    • 2
    • 10
  • Chih-Wei Chou
    • 11
  • Chang-Han Chuang
    • 12
  • Hong-Lin Su
    • 1
    • 15
  • Horng-Jyh Harn
    • 13
    • 14
    Email author
  1. 1.Department of Life Sciences, Agricultural Biotechnology CenterNational Chung Hsing UniversityTaichungChina
  2. 2.Center for NeuropsychiatryChina Medical University and HospitalTaichungChina
  3. 3.Department of NeurosurgeryChina Medical University Beigan HospitalYunlinChina
  4. 4.Department of Neurosurgery, Tainan Municipal An-Nan HospitalChina Medical UniversityTainanChina
  5. 5.Graduate Institute of ImmunologyChina Medical UniversityTaichungChina
  6. 6.Department of Research and DevelopmentGwo Xi Stem Cell Applied Technology Co., Ltd.HsinchuChina
  7. 7.Department of Life Science and Graduate Institute of BiotechnologyNational Dong-Hwa UniversityHualienChina
  8. 8.Double Specialty Program of Management and TechnologyNational Tsing Hua UniversityHsinchuChina
  9. 9.Department of Respiratory TherapyVeterans General Hospital—TaipeiTaipeiChina
  10. 10.Everfront Biotech Inc.New Taipei CityChina
  11. 11.Department of CosmeceuticsChina Medical UniversityTaichungChina
  12. 12.Department of OrthopaedicsNational Cheng Kung University HospitalTainanChina
  13. 13.Department of PathologyChina Medical University HospitalTaichungChina
  14. 14.Department of MedicineChina Medical UniversityTaichungChina
  15. 15.Department of Physical TherapyChina Medical UniversityTaichungChina

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