Ⅱ型cGMP依赖性蛋白激酶抑制VEGFR2介导的人胃癌HGC-27细胞增殖

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Abstract [Abstract]Objective: To investigate the influence of type Ⅱ cGMPdependent protein kinase(PKGⅡ)on proliferation mediated by vascular endothelial growth factor receptor 2(VEGFR2) and its related mechanism in human gastric cancer HGC27 cell line. Methods: The HGC27 cell line was transfected with adenoviral constructs encoding the cDNA of PKGⅡ(AdPKGⅡ) to increase the expression of PKGⅡ, and treated with 8pCPTcGMP to activate the PKGⅡ and treated with vascular endothelial growth factor A (VEGFA) to activate VEGFR2. MTT assay was applied to measure the proliferation activity; Western blotting was used to evaluate the phosphorylation of VEGFR2, Akt and ERK1/2; the interaction between VEGFR2 and PKGⅡwas detected by coimmunoprecipitation;the phosphorylation on serine/threonine(Ser/Thr) of VEGFR2 caused by PKGⅡwas detected by immunoprecipitation and Western blotting. Results: VEGFA treatment caused obvious increase of proliferation and phosphorylation(activation) of VEGFR2, Akt and ERK1/2 in HGC27 cells. In cells transfected with AdPKGⅡto highly express PKGⅡand treated with 8pCPTcGMP, the VEGFA induced increase of proliferation and level of phosphorylation of VEGFR2, Akt and ERK1/2 was significantly inhibited. PKGⅡcould bind with VEGFR2 and cause serine/threonine phosphorylation of the receptor. Conclusion: Activated PKGⅡinhibits the tyrosine phosphorylation(activation) of VEGFR2 through phosphorylating its serine/threonine, subsequently inhibits the proliferation related signal transduction, and finally inhibits the proliferation of human gastric cancer cell line HGC27.

Received: 23 November 2015

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http://zzs.ujs.edu.cn/xbyxb/EN/ OR http://zzs.ujs.edu.cn/xbyxb/EN/Y2016/V26/I02/108

\[1\]Yoo C,Park YS. Companion diagnostics for the targeted therapy of gastric cancer\[J\]. World J Gastroenterol, 2015, 21(39): 10948-10955.
\[2\]Silva SR, Bowen KA, Rychahou PG, et al. VEGFR2 expression in carcinoid cancer cells and its role in tumor growth and metastasis\[J\]. Int J Cancer, 2011, 128(5): 1045-1056.
\[3\]Nakagawa T, Tohyama O, Yamaguchi A, et al. E7050: a dual cMet and VEGFR2 tyrosine kinase inhibitor promotes tumor regression and prolongs survival in mouse xenograft models\[J\]. Cancer Sci, 2010, 101(1): 210-215.
\[4\]Goyal A, Poluzzi C, Willis CD, et al. Endorepellin affects angiogenesis by antagonizing diverse vascular endothelial growth factor receptor 2 (VEGFR2)evoked signaling pathways: transcriptional repression of hypoxiainducible factor 1α and VEGFA and concurrent inhibition of nuclear factor of activated T cell 1 (NFAT1) activation\[J\]. J Biol Chem, 2012, 287(52): 43543-43556.
\[5\]Karamitehrani F, Fallahian F, Atri M. Expression of cGMPdependent protein kinase, PKGⅠα, PKGⅠβ, and PKGⅡ in malignant and benign breast tumors\[J\].Tumour Biol,2012,33(6): 1927-1932.
\[6\]Hofmann F, Ammendola A, Schlossmann J. Rising behind NO: cGMPdependent protein kinases \[J\]. J Cell Sci, 2000, 113(Pt 10): 1671-1676.
\[7\]Bibli SI, Yang G, Zhou Z, et al. Role of cGMP in hydrogen sulfide signaling \[J\]. Nitric Oxide, 2015, 46: 7-13.
\[8\]Cook AL, Haynes JM. Protein kinase GⅡmediated proliferative effects in human cultured prostatic stromal cells \[J\]. Cell Signal, 2004, 16(2): 253-261.
\[9\]Swarting FJ, Ferletta M, Kastemar M, et al. Cyclic GMPdependent protein kinase Ⅱ inhibits cell proliferation, Sox9 expression and Akt phosphorylation in human glioma cell lines \[J\]. Oncogene, 2009, 28(35): 3121-3131.
\[10\]Chen YC, Ren F, Sang JR, et al. Type ⅡcGMPdependent protein kinase inhibits proliferation of the gastric cancer cell line BGC823 \[J\]. Mol Med Rep, 2010, 3(2): 361-366.
\[11\]Ren J, Dong L, Xu CB, et al. The role of KDR in the interactions between human gastric carcinoma cell and vascular endothelial cell \[J\]. World J Gastroenterol, 2002, 8(4): 596-601.
\[12\]Olsson AK, Dimberg A, Kreuger J, et al. VEGF receptor signalling： in control of vascular function\[J\]. NatRev Mol Cell Biol, 2006, 7(5): 359-371.
\[13\]Fournier NM, Lee B, Banasr M, et al. Vascular endothelial growth factor regulates adult hippocampal cell proliferation through MEK/ERK and PI3K/Aktdependent signaling \[J\]. Neuropharmacology, 2012, 63(4): 642-652.
\[14\]Zhang H, Wu J, Meng L, et al. Expression of vascular endothelial growth factor and its receptors KDR and Flt1 in gastric cancer cells \[J\]. World J Gastroenterol, 2002, 8(6): 994-998.
\[15\]Sase H, Watabe T, Kawasaki K, et al.VEGFR2PLCγ1 axis is essential for endothelial specification of VEGFR2+ vascular progenitor cells \[J\]. J Cell Sci, 2009, 122(Pt 18): 3303-3311.
\[16\]Takahashi T, Yamaguchi S, Chida K, et al. A single autophosphorylation site on KDR/Flk1 is essential for VEGFAdependent activation of PLCγ and DNA synthesis in vascular endothelial cells \[J\]. EMBO J, 2001, 20(11): 2768-2778.
\[17\]Wu Y, Chen Y, Qu R, et al. Type Ⅱ cGMPdependent protein kinase inhibits EGFtriggered signal transduction of the MAPK/ERKmediated pathway in gastric cancer cells\[J\].Oncol Rep, 2012, 27(2): 553-558.
\[18\]Kataoka Y, Mukohara T, Tomioka H, et al. Foretinib (GSK1363089), a multikinase inhibitor of MET and VEGFRs, inhibits growth of gastric cancer cell lines by blocking interreceptor tyrosine kinase networks\[J\]. Invest New Drugs, 2012, 30(4): 1352-1360.
\[19\]Jiang L, Lan T, Chen Y, et al. PKG Ⅱ inhibits EGF/EGFRinduced migration of gastric cancer cells\[J\]. PLoS One, 2013, 8(4): e61674.
\[20\]Wu M, Chen Y, Jiang L, et al. Type ⅡcGMPdependent protein kinase inhibits epidermal growth factorinduced phosphatidylinositol3kinase/Akt signal transduction in gastric cancer cells\[J\]. Oncol Lett, 2013, 6(6): 1723-1728.