SYP-5, a novel HIF-1 inhibitor, suppresses tumor cells invasion and angiogenesis.
Hypoxia-inducible factor-1 (HIF-1) plays an essential role in carcinogenesis. The overexpression of HIF-1 induced by hypoxia is closely associated with metastasis, poor prognosis and high mortality. In this study, a novel HIF-1 inhibitor SYP-5 was first observed by the luciferase reporter assay. Western blots results showed SYP-5 inhibited hypoxia-induced upregulation of HIF-1. Moreover, the proteins of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMP)-2 that are targets of HIF-1, were down-regulated by SYP-5. Furthermore, in the tube formation assay, SYP-5 suppressed angiogenesis induced by hypoxia and VEGF in vitro. Additionally, using Transwell and RTCA assays, we found that SYP-5 also retarded the Hep3B and Bcap37 cells migration and invasion induced by hypoxia and FBS. Last, we also detected the upstream pathways related to HIF-1 and found both PI3K/AKT and MAPK/ERK were involved in the SYP-5 mediated invasive inhibition of Bcap37 cells. These results indicates that SYP-5 inhibits tumor cell migration and invasion, as well as tumor angiogenesis, which are mediated by suppressing PI3K/AKT- and MAPK/ERK-dependent HIF-1 pathway. It suggests that SYP-5 might be a potential HIF-1 inhibitor as an anticancer agent.
Department of Pharmacology, Shenyang Pharmaceutical University, 110016 Shenyang, PR China.
Li-Hui
LH
Wang
Department of Pharmacology, Shenyang Pharmaceutical University, 110016 Shenyang, PR China.
Xiao-Rui
XR
Jiang
Department of Pharmacology, Shenyang Pharmaceutical University, 110016 Shenyang, PR China.
Jing-Yu
JY
Yang
Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China.
Xue-Fei
XF
Bao
Department of Pharmacology, Shenyang Pharmaceutical University, 110016 Shenyang, PR China.
Jun-Li
JL
Chen
Department of Pharmacology, Shenyang Pharmaceutical University, 110016 Shenyang, PR China.
Xing
X
Liu
Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China. Electronic address: guoliang222@gmail.com.
Guo-Liang
GL
Chen
Department of Pharmacology, Shenyang Pharmaceutical University, 110016 Shenyang, PR China. Electronic address: wucf@syphu.edu.cn.
Chun-Fu
CF
Wu
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001578:Benzopyrans / Q000494:pharmacology* / Q000627:therapeutic use; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D055806:Microvessels / Q000187:drug effects / Q000473:pathology; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000091402:Prohibitins; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology* / Q000627:therapeutic use; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D000970:Antineoplastic Agents; D001578:Benzopyrans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019869:Phosphatidylinositol 3-Kinases; D000091402:Prohibitins; D051057:Proto-Oncogene Proteins c-akt; D013876:Thiophenes; D042461:Vascular Endothelial Growth Factor A; C497442:HIF1A protein, human; C000717331:PHB2 protein, human; C000616515:SYP-5 compound
Angiogenesis; HIF-1; Invasion; MAPK pathway; PI3K/AKT pathway; SYP-5