Silibinin-induced glioma cell apoptosis by PI3K-mediated but Akt-independent downregulation of FoxM1 expression.
The oncogenic transcription factor Forkhead box M1 (FoxM1) is overexpressed in many human tumors, including glioma. As a critical regulator of the cell cycle and apoptosis-related genes, FoxM1 is a potential therapeutic target against human malignant glioma. Silibinin, a flavonoid isolated from Silybum marianum, dose-dependently reduced glioma cell proliferation, promoted apoptosis, and downregulated FoxM1 expression. Knockdown of FoxM1 by small hairpin RNA (shRNA) transfection also promoted glioma cell apoptosis and augmented the antiproliferative and pro-apoptotic properties of silibinin. Moreover, silibinin increased caspase-3 activation, upregulated pro-apoptotic Bax, and suppressed anti-apoptotic Bcl-2 expression, effects enhanced by FoxM1 knockdown. Silibinin treatment suppressed U87 cell PI3K phospho-activation, and simultaneous silibinin exposure, FoxM1 knockdown, and PI3K inhibition additively increased U87 cell apoptosis. Furthermore, PI3K inhibition reduced FoxM1 expression. Akt activity was also suppressed by FoxM1 downregulation but Akt inhibition did not alter FoxM1 expression. Thus, silibinin likely inhibited glioma cell proliferation and induced apoptosis through inactivation of PI3K and FoxM1, leading to activation of the mitochondrial apoptotic pathway. FoxM1 may be a novel target for chemotherapy against human glioma.
Department of Neurosurgery, Shengjing Hospital, China Medical University, Shenyang, Liaoning Province 110004, PR China.
Mingjie
M
Zhang
Department of Neurosurgery, Shengjing Hospital, China Medical University, Shenyang, Liaoning Province 110004, PR China. Electronic address: yunhuiliu777@126.com.
Yunhui
Y
Liu
He University, Shenyang, Liaoning Province 110163, PR China.
Yun
Y
Gao
Department of Neurosurgery, Shengjing Hospital, China Medical University, Shenyang, Liaoning Province 110004, PR China.
Shaoyi
S
Li
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000378:metabolism*; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology*
D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D000077385:Silybin; D012838:Silymarin; C107585:FOXM1 protein, human
Akt; FoxM1; PI3K; Silibinin; apoptosis