Paeoniflorin inhibits human glioma cells via STAT3 degradation by the ubiquitin-proteasome pathway.
We investigated the underlying mechanism for the potent proapoptotic effect of paeoniflorin (PF) on human glioma cells in vitro, focusing on signal transducer and activator of transcription 3 (STAT3) signaling. Significant time- and dose-dependent apoptosis and inhibition of proliferation were observed in PF-treated U87 and U251 glioma cells. Expression of STAT3, its active form phosphorylated STAT3 (p-STAT3), and several downstream molecules, including HIAP, Bcl-2, cyclin D1, and Survivin, were significantly downregulated upon PF treatment. Overexpression of STAT3 induced resistance to PF, suggesting that STAT3 was a critical target of PF. Interestingly, rapid downregulation of STAT3 was consistent with its accelerated degradation, but not with its dephosphorylation or transcriptional modulation. Using specific inhibitors, we demonstrated that the prodegradation effect of PF on STAT3 was mainly through the ubiquitin-proteasome pathway rather than via lysosomal degradation. These findings indicated that PF-induced growth suppression and apoptosis in human glioma cells through the proteasome-dependent degradation of STAT3.
Affiliated Bayi Brain Hospital, Southern Medical University, Beijing, People's Republic of China.
Xiao-hu
XH
Nie
Nanchang University Medical College, Jiangxi, People's Republic of China.
Jia
J
Ou-yang
Department of Gastroenterology, The 98th Hospital of Nanjing Military Command, Huzhou, Zhejiang, People's Republic of China.
Ying
Y
Xing
Spleen & Stomach Institution, Guangzhou University of Traditional Chinese Medicine, Guangdong, People's Republic of China.
Dan-yan
DY
Li
Affiliated Bayi Brain Hospital, Southern Medical University, Beijing, People's Republic of China.
Xing-yu
XY
Dong
Department of Neurosurgery, China-Japan Friendship Hospital, Beijing, People's Republic of China.
Ru-en
RE
Liu
Bayi Brain Hospital, The Military General Hospital of Beijing PLA, Beijing, People's Republic of China.
Ru-xiang
RX
Xu
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005910:Glioma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D005960:Glucosides / Q000494:pharmacology*; D006801:Humans; D039821:Monoterpenes / Q000494:pharmacology*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D059748:Proteolysis; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism*; D054875:Ubiquitination; D006027:Glycosides
D000972:Antineoplastic Agents, Phytogenic; D005960:Glucosides; D039821:Monoterpenes; D046988:Proteasome Endopeptidase Complex; D050796:STAT3 Transcription Factor; D025801:Ubiquitin; C494086:STAT3 protein, human; C015423:peoniflorin; D006027:Glycosides
apoptosis; glioma; paeoniflorin; proliferation; signal transducer and activator of transcription 3 (STAT3); ubiquitin–proteasome pathway (UPP)