Hispidulin potently inhibits human glioblastoma multiforme cells through activation of AMP-activated protein kinase (AMPK).
Glioblastoma multiforme (GBM) is the most common and lethal type of primary brain tumor. Despite recent therapeutic advances in other cancers, the treatment of GBM remains ineffective and essentially palliative. The current focus lies in the finding of components that activate the AMP-activated protein kinase (AMPK), one key enzyme thought to be activated during the caloric restriction (CR). In the present study, we found that treatment of hispidulin, a flavone isolated from Saussurea involucrate Kar. et Kir., resulted in dose-dependent inhibition of GBM cellular proliferation. Interestingly, we show that hispidulin activated AMPK in GBM cells. The activation of AMPK suppressed downstream substrates, such as the mammalian target of rapamycin (mTOR) and eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), and resulted in a general decrease in mRNA translation. Moreover, hispidulin-activated AMPK decreases the activity and/or expression of lipogenic enzymes, such as fatty acid synthase (FASN) and acetyl-CoA carboxylase (ACC). Furthermore, hispidulin blocked the progression of the cell cycle at the G1 phase and induced apoptosis by inducing p53 expression and further upregulating p21 expression in GBM cells. On the basis of these results, we demonstrated that hispidulin has the potential to be a chemopreventive and therapeutic agent against human GBM.
Lin
Ying-Chao
YC
Institute of Biochemistry, College of Life Science, National Chung Hsing University, Taichung, Taiwan.
Hung
Chao-Ming
CM
Tsai
Jia-Chun
JC
Lee
Jang-Chang
JC
Chen
Yi-Lin Sophia
YL
Wei
Chyou-Wei
CW
Kao
Jung-Yie
JY
Way
Tzong-Der
TD
D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000201:enzymology / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D047309:Flavones / Q000494:pharmacology*; D005909:Glioblastoma / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*
D047309:Flavones; D051057:Proto-Oncogene Proteins c-akt; C055957:hispidulin