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

Cancer Research - Tập 70 Số 5 - Trang 1951-1959 - 2010
Xiufeng Pang1, Zhengfang Yi1, Jing Zhang1, Binbin Lu1, Bokyung Sung1, Weijing Qu1, Bharat B. Aggarwal1, Mingyao Liu1
1Authors' Affiliations: 1Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China and 2Institute of Biosciences and Technology, Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center; 3Department of Experimental Therapeutics, Cytokine Research Laboratory, University of Texas M.D. Anderson Cancer Center, Houston, Texas

Tóm tắt

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 Celastrol could inhibit angiogenesis-mediated tumor growth and, if so, through what mechanism. When given s.c. 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 vascular endothelial cells (HUVEC) in a dose-dependent manner. Furthermore, 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/P70S6K signaling. Taken together, our results suggest that Celastrol targets the AKT/mTOR/P70S6K pathway, which leads to suppression of tumor growth and angiogenesis. Cancer Res; 70(5); 1951–9

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Cancer Research

Tập 70 Số 5

1951-1959

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