title: Dual inhibition of plasminogen kringle 5 on angiogenesis and chemotaxis suppresses tumor metastasis by targeting HIF-1α pathway.
abstract: We had demonstrated that plasminogen kringle 5 (K5), a potent angiogenic inhibitor, inhibited retinal neovascularization and hepatocellular carcinoma growth by anti-angiogenesis. The current study investigated the effects and the underlying mechanisms of K5 on both tumor growth and spontaneous pulmonary metastasis in Lewis lung carcinoma (LLC) implanted mouse model. Similarly, K5 could decrease expression of VEGF in LLC cells and grafted tissues and suppress tumor angiogenesis and growth. K5 had no direct effect on proliferation and apoptosis of LLC. However, K5 could significantly inhibit SDF-1α-induced chemotaxis movement of LLC cells and resulted in a great reduction of surface metastatic nodules and micrometastases in the lungs of LLC tumor-bearing mice. K5 also decreased expression of chemokine (C-X-C motif) receptor 4 (CXCR4) in LLC cells and grafted tissues. Furthermore, K5 down-regulated SDF-1α expression in metastatic lung tissues of LLC-bearing mice. Therefore, K5 may suppress tumor pulmonary metastasis through inhibiting SDF-1α-CXCR4 chemotaxis movement and down-regulation of VEGF. Moreover, the role of hypoxia inducible factor-1α (HIF-1α), a crucial transcriptional factor for both VEGF and CXCR4 expression, was evaluated. The siRNA of HIF-1α attenuated expression of VEGF and CXCR4 and inhibited LLC migration. K5 decreased HIF-1α protein level and impaired nuclear HIF-1α accumulation. These results showed for the first time that K5 inhibits LLC growth and metastasis via the dual effects of anti-angiogenesis and suppression of tumor cell motility by targeting the pivotal molecule, HIF-1α.
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Wei-Bin
authors.initials: WB
authors.lastname: Cai
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Rui
authors.initials: R
authors.lastname: Cheng
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.forename: Shu-Huan
authors.initials: SH
authors.lastname: Fang
authors.forename: Zu-Min
authors.initials: ZM
authors.lastname: Xu
authors.forename: Xia
authors.initials: X
authors.lastname: Yang
authors.forename: Zhong-Han
authors.initials: ZH
authors.lastname: Yang
authors.forename: Jian-Xing
authors.initials: JX
authors.lastname: Ma
authors.forename: Chun-Kui
authors.initials: CK
authors.lastname: Shao
authors.forename: Guo-Quan
authors.initials: GQ
authors.lastname: Gao
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D018827:Carcinoma, Lewis Lung / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology* / Q000627:therapeutic use; D010958:Plasminogen / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D054377:Chemokine CXCL12; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010446:Peptide Fragments; D042461:Vascular Endothelial Growth Factor A; C491499:plasminogen kringle 5; D010958:Plasminogen