Journal Article

Tanshinone IIA Inhibits HIF-1α and VEGF Expression in Breast Cancer Cells via mTOR/p70S6K/RPS6/4E-BP1 Signaling Pathway

Gao, Ning, Shan, Changyu, Cui, Hongjuan, Zhou, Jing, Hu, Xiaoye, Li, Guobing, Zhou, Ting, Liu, Lei, Chen, Yibiao

2015

Overview

Hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) play important roles in angiogenesis and tumor growth. Tanshinone IIA (T2A) is a novel antiangiogenic agent with promising antitumor effects; however, the molecular mechanism underlying the antiangiogenic effects of T2A remains unclear. In the present study, we provided evidence showing that T2A inhibited angiogenesis and breast cancer growth by down-regulating VEGF expression. Specifically, T2A repressed HIF-1α expression at the translational level and inhibited the transcriptional activity of HIF-1α, which led to the down-regulation of VEGF expression. Suppression of HIF-1α synthesis by T2A correlated with strong dephosphorylation of mammalian target of rapamycin (mTOR) and its effectors ribosomal protein S6 kinase (p70S6K) and eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), a pathway regulating HIF-1α expression at the translational level. In addition, we also found that T2A inhibited the angiogenesis and growth of human breast cancer xenografts in nude mice through suppression of HIF-1α and VEGF. Our study provides novel perspectives and potential targets for the treatment of human breast cancer.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Abietanes - pharmacology / Adaptor Proteins, Signal Transducing - metabolism / Angiogenesis / Animals / Antiangiogenics / Anticancer properties / Antineoplastic Agents, Phytogenic / Antitumor activity / Biology / Breast cancer / Breast Neoplasms - drug therapy / Breast Neoplasms - metabolism / Breast Neoplasms - pathology / Cancer / Cancer therapies / Cell Cycle Proteins / Cell Line, Tumor / Chemotherapy / Dephosphorylation / Enzymes / Epigenetics / Female / Gene expression / Gene Expression Regulation, Neoplastic / Genomes / Humans / Hypoxia / Hypoxia-Inducible Factor 1, alpha Subunit - biosynthesis / Hypoxia-inducible factors / Immunoglobulins / Inhibition / Initiation factor eIF-4E / Kinases / Laboratories / Medical prognosis / Metastasis / Mice / Mice, Nude / Molecular chains / Neoplasm Proteins - metabolism / Neovascularization, Pathologic - drug therapy / Neovascularization, Pathologic - metabolism / Neovascularization, Pathologic - pathology / Pharmacy / Phosphoproteins - metabolism / Proteins / Rapamycin / Ribosomal protein S6 / Ribosomal Protein S6 - metabolism / Ribosomal protein S6 kinase / Ribosomal Protein S6 Kinases, 70-kDa - metabolism / Signal transduction / Signal Transduction - drug effects / TOR protein / TOR Serine-Threonine Kinases - metabolism / Transcription / Tumors / Vascular endothelial growth factor / Vascular Endothelial Growth Factor A - biosynthesis / Xenograft Model Antitumor Assays / Xenografts / Xenotransplantation