Tanshinone IIA inhibits beta-catenin/VEGF-mediated angiogenesis by targeting TGF-beta 1 in normoxic and HIF-1 alpha in hypoxic microenvironments in human colorectal cancer

摘要

In a previous study, we demonstrated that Tanshinone IIA effectively inhibits CRC angiogenesis in vivo, but the underlying mechanisms were not elucidated. In this report, we describe experiments in which HIF-1 alpha levels were manipulated to probe the effect of hypoxia on CRC cell angiogenesis. We studied the effects of Tan IIA on CRC pro-angiogenic factor and on human umbilical vein endothelial cell angiogenesis in normoxia and hypoxia. Our results show that Tan IIA not only lowers HIF-1 alpha levels and inhibits secretion of VEGF and bFGF, but also efficiently suppresses the proliferation, tube formation and metastasis of HUVECs. Interruption of the HIF-1 alpha/beta-cateniniTCF3/LEF1 signaling pathway occurs in the hypoxic microenvironment. The mechanism involves HIF-1a inhibition of TGF-beta 1 secretion, which drives angiogenesis by promoting B-catenin nuclear localization and TCF/LEF activation. To test an improved delivery system for Tan IIA, we loaded the drug into mesoporous silica nanoparticles (MSN-NH2) and found that it effectively targets HIF-1a overexpression in a mouse colon tumor model. Finally, Tan IIA sodium sulfonate exhibits anti-angiogenesis activity in CRC patients by reducing levels of angiogenin, VEGF and bFGF expression. Our research provides a new anti-angiogenesis strategy and strengthens support for the use of Tan IIA as an angiogenesis inhibitor. (C) 2017 Elsevier B.V. All rights reserved.