Brain tumor senescence might be mediated by downregulation of S-phase kinase-associated protein 2 via butylidenephthalide leading to decreased cell viability.
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.
Department of Life Sciences, Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Taiwan, Republic of China.
Mao-Hsuan
MH
Huang
Shinn-Zong
SZ
Lin
Po-Cheng
PC
Lin
Tzyy-Wen
TW
Chiou
Yeu-Wei
YW
Harn
Li-Ing
LI
Ho
Tzu-Min
TM
Chan
Chih-Wei
CW
Chou
Chang-Han
CH
Chuang
Hong-Lin
HL
Su
Horng-Jyh
HJ
Harn
D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D015536:Down-Regulation; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010796:Phthalic Anhydrides / Q000494:pharmacology*; D000090063:Proto-Oncogene Mas; D044786:S-Phase Kinase-Associated Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D016329:Sp1 Transcription Factor / Q000378:metabolism
C000715470:MAS1 protein, human; D010796:Phthalic Anhydrides; D000090063:Proto-Oncogene Mas; D044786:S-Phase Kinase-Associated Proteins; D016329:Sp1 Transcription Factor; C026105:butylidenephthalide