NDLI: Celastrol Suppresses Angiogenesis-Mediated Tumor Growth through Inhibition of AKT/Mammalian Target of Rapamycin Pathway

Content Provider	PubMed Central
Author	Pang, Xiufeng Yi, Zhengfang Zhang, Jing Lu, Binbin Sung, Bokyung Qu, Weijing Aggarwal, Bharat B. Liu, Mingyao
Abstract	Understanding the molecular basis and target of traditional medicine is critical for drug development. Celastrol, derived from Trypterygium wilfordii Hook F. (“Thunder of God Vine”), a traditional Chinese medicine plant, has been assigned anticancer activities but its mechanism is not well understood. Here, we investigated whether Celestrol could inhibit angiogenesis-mediated tumor growth and if so through what mechanism. When administered subcutaneously to mice bearing human prostate cancer (PC-3 cell) xenografts, Celastrol (2 mg/kg/d) significantly reduced the volume and the weight of solid tumors and decreased tumor angiogenesis. We found that this agent inhibited vascular endothelial growth factor (VEGF)-induced proliferation, migration, invasion, and capillary-like structure formation by primary cultured human umbilical endothelial cells (HUVECs) in a dose-dependent manner. Further, Celastrol abrogated VEGF-induced sprouting of the vessels from aortic rings and inhibited vascular formation in the Matrigel plug assay in vivo. To understand the molecular mechanism of these activities, we next examined the signaling pathways in treated HUVECs and PC-3 tumor cells. Celastrol suppressed the VEGF-induced activation of AKT, mammalian target of rapamycin (mTOR), and ribosomal protein S6 kinase (P70S6K). Additionally, we found that Celastrol inhibited the proliferation of prostate cancer cells and induced apoptosis, and these effects correlated with the extent of inhibition of AKT/mTOR/P70S6 kinase signaling. Taken together, our results suggest that Celastrol targets the AKT/mTOR/P70S6K pathway, which leads to suppression of tumor growth and angiogenesis.
Related Links	http://dx.doi.org/10.1158/0008-5472.can-09-3201
Ending Page	1959
Page Count	9
Starting Page	1951
File Format	PDF
ISSN	00085472
e-ISSN	15387445
Journal	Cancer research
Issue Number	5
Volume Number	70
Language	English
Publisher Date	2010-03-01
Access Restriction	Open
Subject Keyword	Cancer Research Oncology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cancer Research Oncology

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