SpringerLink
Log in

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

  • Research Article
  • Published:
Tumor Biology

Abstract

Develo** 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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Germany)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

BP:

Butylidenephthalide

GBM:

Glioblastoma multiform

Skp2:

S-phase kinase-associated protein 2

References

  1. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007;114(2):97–109. doi:10.1007/s00401-007-0243-4.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Assanah M, Lochhead R, Ogden A, Bruce J, Goldman J, Canoll P. Glial progenitors in adult white matter are driven to form malignant gliomas by platelet-derived growth factor-expressing retroviruses. J Neurosci Off J Soc Neurosci. 2006;26(25):6781–90. doi:10.1523/JNEUROSCI.0514-06.2006.

    Article  CAS  Google Scholar 

  3. Levin VA. Neuro-oncology: an overview. Arch Neurol. 1999;56(4):401–4.

    Article  CAS  PubMed  Google Scholar 

  4. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352(10):997–1003. doi:10.1056/NEJMoa043331.

    Article  CAS  PubMed  Google Scholar 

  5. Giese A, Bjerkvig R, Berens ME, Westphal M. Cost of migration: invasion of malignant gliomas and implications for treatment. J Clin Oncol Off J Am Soc Clin Oncol. 2003;21(8):1624–36. doi:10.1200/JCO.2003.05.063.

    Article  CAS  Google Scholar 

  6. Sathornsumetee S, Rich JN. New treatment strategies for malignant gliomas. Expert Rev Anticancer Ther. 2006;6(7):1087–104. doi:10.1586/14737140.6.7.1087.

    Article  CAS  PubMed  Google Scholar 

  7. Reardon DA, Wen PY. Therapeutic advances in the treatment of glioblastoma: rationale and potential role of targeted agents. Oncologist. 2006;11(2):152–64. doi:10.1634/theoncologist.11-2-152.

    Article  CAS  PubMed  Google Scholar 

  8. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987–96. doi:10.1056/NEJMoa043330.

    Article  CAS  PubMed  Google Scholar 

  9. Tsai NM, Lin SZ, Lee CC, Chen SP, Su HC, Chang WL, et al. The antitumor effects of Angelica sinensis on malignant brain tumors in vitro and in vivo. Clin Cancer Res. 2005;11(9):3475–84. doi:10.1158/1078-0432.CCR-04-1827.

    Article  PubMed  Google Scholar 

  10. Tsai NM, Chen YL, Lee CC, Lin PC, Cheng YL, Chang WL, et al. The natural compound n-butylidenephthalide derived from Angelica sinensis inhibits malignant brain tumor growth in vitro and in vivo. J Neurochem. 2006;99(4):1251–62. doi:10.1111/j.1471-4159.2006.04151.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lin PC, Chen YL, Chiu SC, Yu YL, Chen SP, Chien MH, et al. Orphan nuclear receptor, Nurr-77 was a possible target gene of butylidenephthalide chemotherapy on glioblastoma multiform brain tumor. J Neurochem. 2008;106(3):1017–26. doi:10.1111/j.1471-4159.2008.05432.x.

    Article  CAS  PubMed  Google Scholar 

  12. Chen Z, Trotman LC, Shaffer D, Lin HK, Dotan ZA, Niki M, et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature. 2005;436(7051):725–30. doi:10.1038/nature03918.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Collado M, Gil J, Efeyan A, Guerra C, Schuhmacher AJ, Barradas M, et al. Tumour biology: senescence in premalignant tumours. Nature. 2005;436(7051):642. doi:10.1038/436642a.

    Article  CAS  PubMed  Google Scholar 

  14. Nakayama KI, Nakayama K. Regulation of the cell cycle by SCF-type ubiquitin ligases. Semin Cell Dev Biol. 2005;16(3):323–33. doi:10.1016/j.semcdb.2005.02.010.

    Article  CAS  PubMed  Google Scholar 

  15. Bloom J, Pagano M. Deregulated degradation of the cdk inhibitor p27 and malignant transformation. Semin Cancer Biol. 2003;13(1):41–7.

    Article  CAS  PubMed  Google Scholar 

  16. Kipreos ET, Pagano M. The F-box protein family. Reviews. 2000;1(5):3002. doi:10.1186/gb-2000-1-5-reviews3002.

    Google Scholar 

  17. Westermann F, Henrich KO, Wei JS, Lutz W, Fischer M, Konig R, et al. High Skp2 expression characterizes high-risk neuroblastomas independent of MYCN status. Clin Cancer Res Off J Am Assoc Cancer Res. 2007;13(16):4695–703. doi:10.1158/1078-0432.CCR-06-2818.

    Article  CAS  Google Scholar 

  18. Chiappetta G, De Marco C, Quintiero A, Califano D, Gherardi S, Malanga D, et al. Overexpression of the S-phase kinase-associated protein 2 in thyroid cancer. Endocr Relat Cancer. 2007;14(2):405–20. doi:10.1677/ERC-06-0030.

    Article  CAS  PubMed  Google Scholar 

  19. Sonoda H, Inoue H, Ogawa K, Utsunomiya T, Masuda TA, Mori M. Significance of skp2 expression in primary breast cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2006;12(4):1215–20. doi:10.1158/1078-0432.CCR-05-1709.

    Article  CAS  Google Scholar 

  20. Lloyd RV. Molecular pathology of pituitary adenomas. J Neuro-Oncol. 2001;54(2):111–9.

    Article  CAS  Google Scholar 

  21. Lin HK, Chen Z, Wang G, Nardella C, Lee SW, Chan CH, et al. Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence. Nature. 2010;464(7287):374–9. doi:10.1038/nature08815.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wei Z, Jiang X, Liu F, Qiao H, Zhou B, Zhai B, et al. Downregulation of Skp2 inhibits the growth and metastasis of gastric cancer cells in vitro and in vivo. Tumour Biol J Int Soc Oncodev Biol Med. 2013;34(1):181–92. doi:10.1007/s13277-012-0527-8.

    Article  CAS  Google Scholar 

  23. Zuo T, Liu R, Zhang H, Chang X, Liu Y, Wang L, et al. FOXP3 is a novel transcriptional repressor for the breast cancer oncogene SKP2. J Clin Invest. 2007;117(12):3765–73. doi:10.1172/JCI32538.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Imaki H, Nakayama K, Delehouzee S, Handa H, Kitagawa M, Kamura T, et al. Cell cycle-dependent regulation of the Skp2 promoter by GA-binding protein. Cancer Res. 2003;63(15):4607–13.

    CAS  PubMed  Google Scholar 

  25. Cheng YL, Chang WL, Lee SC, Liu YG, Chen CJ, Lin SZ, et al. Acetone extract of Angelica sinensis inhibits proliferation of human cancer cells via inducing cell cycle arrest and apoptosis. Life Sci. 2004;75(13):1579–94. doi:10.1016/j.lfs.2004.03.009.

    Article  CAS  PubMed  Google Scholar 

  26. Chen YL, Jian MH, Lin CC, Kang JC, Chen SP, Lin PC, et al. The induction of orphan nuclear receptor nur77 expression by n-butylenephthalide as pharmaceuticals on hepatocellular carcinoma cell therapy. Mol Pharmacol. 2008;74(4):1046–58. doi:10.1124/mol.107.044800.

    Article  CAS  PubMed  Google Scholar 

  27. Liu PY, Sheu JJ, Lin PC, Lin CT, Liu YJ, Ho LI, et al. Expression of Nur77 induced by an n-butylidenephthalide derivative promotes apoptosis and inhibits cell growth in oral squamous cell carcinoma. Invest New Drugs. 2012;30(1):79–89. doi:10.1007/s10637-010-9518-z.

    Article  CAS  PubMed  Google Scholar 

  28. Carrano AC, Pagano M. Role of the F-box protein Skp2 in adhesion-dependent cell cycle progression. J Cell Biol. 2001;153(7):1381–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Latres E, Chiarle R, Schulman BA, Pavletich NP, Pellicer A, Inghirami G, et al. Role of the F-box protein Skp2 in lymphomagenesis. Proc Natl Acad Sci U S A. 2001;98(5):2515–20. doi:10.1073/pnas.041475098.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wang IC, Chen YJ, Hughes D, Petrovic V, Major ML, Park HJ, et al. Forkhead box M1 regulates the transcriptional network of genes essential for mitotic progression and genes encoding the SCF (Skp2-Cks1) ubiquitin ligase. Mol Cell Biol. 2005;25(24):10875–94. doi:10.1128/MCB.25.24.10875-10894.2005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

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

None

Author information

Authors and Affiliations

  1. Department of Life Sciences, Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Taiwan, China

    Mao-Hsuan Huang & Hong-Lin Su

  2. Center for Neuropsychiatry, China Medical University and Hospital, Taichung, Taiwan, China

    Shinn-Zong Lin & Tzu-Min Chan

  3. Department of Neurosurgery, China Medical University Beigan Hospital, Yunlin, Taiwan, China

    Shinn-Zong Lin

  4. Department of Neurosurgery, Tainan Municipal An-Nan Hospital, China Medical University, Tainan, Taiwan, China

    Shinn-Zong Lin

  5. Graduate Institute of Immunology, China Medical University, Taichung, Taiwan, China

    Shinn-Zong Lin

  6. Department of Research and Development, Gwo ** Stem Cell Applied Technology Co., Ltd., Hsinchu, Taiwan, China

    Po-Cheng Lin

  7. Department of Life Science and Graduate Institute of Biotechnology, National Dong-Hwa University, Hualien, Taiwan, China

    Tzyy-Wen Chiou

  8. Double Specialty Program of Management and Technology, National Tsing Hua University, Hsinchu, Taiwan, China

    Yeu-Wei Harn

  9. Department of Respiratory Therapy, Veterans General Hospital—Taipei, Taipei, Taiwan, China

    Li-Ing Ho

  10. Everfront Biotech Inc., New Taipei City, Taiwan, China

    Tzu-Min Chan

  11. Department of Cosmeceutics, China Medical University, Taichung, Taiwan, China

    Chih-Wei Chou

  12. Department of Orthopaedics, National Cheng Kung University Hospital, Tainan, Taiwan, China

    Chang-Han Chuang

  13. Department of Pathology, China Medical University Hospital, No. 2, Yuh-Der Rd., Taichung, Taiwan, 40447, China

    Horng-Jyh Harn

  14. Department of Medicine, China Medical University, Taichung, Taiwan, China

    Horng-Jyh Harn

  15. Department of Physical Therapy, China Medical University, Taichung, Taiwan, China

    Hong-Lin Su

Authors
  1. Mao-Hsuan Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shinn-Zong Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Po-Cheng Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tzyy-Wen Chiou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yeu-Wei Harn
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Li-Ing Ho
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tzu-Min Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chih-Wei Chou
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Chang-Han Chuang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hong-Lin Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Horng-Jyh Harn
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Horng-Jyh Harn.

Additional information

H.-L. Su and H.-J. Harn contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Huang, MH., Lin, SZ., Lin, PC. et al. Brain tumor senescence might be mediated by downregulation of S-phase kinase-associated protein 2 via butylidenephthalide leading to decreased cell viability. Tumor Biol. 35, 4875–4884 (2014). https://doi.org/10.1007/s13277-014-1639-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-014-1639-0

Keyword

Search

Navigation