title: Tanshinone IIA inhibits HIF-1α and VEGF expression in breast cancer cells via mTOR/p70S6K/RPS6/4E-BP1 signaling pathway.
abstract: 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.
authors: College of Pharmacy, Third Military Medical University, Chongqing, China.
authors: Guobing
authors: G
authors: Li
authors: College of Pharmacy, Third Military Medical University, Chongqing, China.
authors: Changyu
authors: C
authors: Shan
authors: College of Pharmacy, Third Military Medical University, Chongqing, China.
authors: Lei
authors: L
authors: Liu
authors: College of Pharmacy, Third Military Medical University, Chongqing, China.
authors: Ting
authors: T
authors: Zhou
authors: College of Pharmacy, Third Military Medical University, Chongqing, China.
authors: Jing
authors: J
authors: Zhou
authors: College of Pharmacy, Third Military Medical University, Chongqing, China.
authors: Xiaoye
authors: X
authors: Hu
authors: State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China.
authors: Yibiao
authors: Y
authors: Chen
authors: State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China.
authors: Hongjuan
authors: H
authors: Cui
authors: College of Pharmacy, Third Military Medical University, Chongqing, China.
authors: Ning
authors: N
authors: Gao
mesh_terms: D045784:Abietanes / Q000494:pharmacology*; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010750:Phosphoproteins / Q000378:metabolism*; D038601:Ribosomal Protein S6 / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*; D023041:Xenograft Model Antitumor Assays
chemical_list: D045784:Abietanes; D048868:Adaptor Proteins, Signal Transducing; D000972:Antineoplastic Agents, Phytogenic; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D038601:Ribosomal Protein S6; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C021751:tanshinone; C546842:MTOR protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases