sMEK1 inhibits endothelial cell proliferation by attenuating VEGFR-2-dependent-Akt/eNOS/HIF-1α signaling pathways

Oncotarget

Volumn 6, Issue 31, 2015, Pages 31830-31843

  Kim, Boh Ram ^a,c   Seo, Seung Hee ^a   Park, Mi Sun ^a   Lee, Seung Hoon ^b   Kwon, Youngjoo ^c   Rho, Seung Bae ^a  

^a National Cancer Center   (South Korea)

^b Yongin University   (South Korea)

^c Ewha Womans University   (South Korea)

Author keywords

Anti angiogenic activity; Hypoxic condition; Ovarian tumor; sMEK1 tumor suppressor; Xenograft model

Indexed keywords

ANGIOGENESIS INHIBITOR; ENDOTHELIAL NITRIC OXIDE SYNTHASE; HYPOXIA INDUCIBLE FACTOR 1ALPHA; PHOSPHOINOSITIDE DEPENDENT PROTEIN KINASE 1; PHOSPHOLIPASE C GAMMA1; PROTEIN KINASE B; SUPPRESSOR OF MEK 1 NULL PROTEIN; UNCLASSIFIED DRUG; VASCULOTROPIN RECEPTOR 1; VASCULOTROPIN RECEPTOR 2; HIF1A PROTEIN, HUMAN; NOS3 PROTEIN, HUMAN; PHOSPHOPROTEIN PHOSPHATASE; SMEK1 PROTEIN, HUMAN; VASCULOTROPIN A; VEGFA PROTEIN, HUMAN;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTINEOPLASTIC ACTIVITY; ANTIPROLIFERATIVE ACTIVITY; ARTICLE; CANCER GROWTH; CANCER INHIBITION; CELL FUNCTION; CELL STIMULATION; CELL STRUCTURE; CONTROLLED STUDY; ENDOTHELIUM CELL; FEMALE; HUMAN; HUMAN CELL; IN VITRO STUDY; IN VIVO STUDY; INHIBITION KINETICS; MIGRATION INHIBITION; MOUSE; NONHUMAN; OVARY CARCINOMA; PROTEIN ANALYSIS; PROTEIN BINDING; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; PROTEIN PROTEIN INTERACTION; SIGNAL TRANSDUCTION; TUMOR VASCULARIZATION; UMBILICAL VEIN ENDOTHELIAL CELL; ANIMAL; APOPTOSIS; BAGG ALBINO MOUSE; CELL CULTURE; CELL MOTION; CELL PROLIFERATION; DRUG SCREENING; ENZYME IMMUNOASSAY; IMMUNOPRECIPITATION; METABOLISM; NEOVASCULARIZATION (PATHOLOGY); NUDE MOUSE; OVARY TUMOR; PATHOLOGY; PHOSPHORYLATION; WESTERN BLOTTING;

ANIMALS; APOPTOSIS; BLOTTING, WESTERN; CELL MOVEMENT; CELL PROLIFERATION; CELLS, CULTURED; FEMALE; HUMAN UMBILICAL VEIN ENDOTHELIAL CELLS; HUMANS; HYPOXIA-INDUCIBLE FACTOR 1, ALPHA SUBUNIT; IMMUNOENZYME TECHNIQUES; IMMUNOPRECIPITATION; MICE; MICE, INBRED BALB C; MICE, NUDE; NEOVASCULARIZATION, PATHOLOGIC; NITRIC OXIDE SYNTHASE TYPE III; OVARIAN NEOPLASMS; PHOSPHOPROTEIN PHOSPHATASES; PHOSPHORYLATION; PROTO-ONCOGENE PROTEINS C-AKT; SIGNAL TRANSDUCTION; VASCULAR ENDOTHELIAL GROWTH FACTOR A; VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR-2; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 84945535957     PISSN: None     EISSN: 19492553     Source Type: Journal    
DOI: 10.18632/oncotarget.5570     Document Type: Article

References (74)

1. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat. Med. 1995; 1: 27-31.
2. Izumi Y, Xu L, Tomaso ED, Fukumura D, Jain RK. Tumour biology: herceptin acts as an anti-angiogenic cocktail. Nature 2002; 416: 279-280.
3. Ongusaha PP, Kwak JC, Zwible AJ, Macip S, Higashiyama S, Taniguchi N, Fang L, Lee SW. HB-EGF is a potent inducer of tumor growth and angiogenesis. Cancer Res. 2004; 64: 5283-5290.
4. Watanabe K, Hasegawa Y, Yamashita H, Shimizu K, Ding Y, Abe M, Ohta H, Imagawa K, Hojo K, Maki H, Sonoda H, Sato Y. Vasohibin as an endothelium-derived negative feedback regulator of angiogenesis. J. Clin. Invest. 2004; 114: 898-907.
5. Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J. Clin. Oncol. 2005; 23: 1011-1027.
6. Poveshchenko AF, Konenkov VI. Mechanisms and factors of angiogenesis. Usp. Fiziol. Nauk 2010; 41: 68-89.
7. Ruf W, Yokota N, Schaffner F. Tissue factor in cancer progression and angiogenesis. Thromb. Res. 2010; 125: S36-38.
8. Saharinen P, Eklund L, Pulkki K, BonoK P, Alitalo K. VEGF and angiopoietin signaling in tumor angiogenesis and metastasis. Trends Mol. Med. 2011; 17: 347-362.
9. Kiselyov A, Balakin KV, Tkachenko SE. VEGF/VEGFR signalling as a target for inhibiting angiogenesis. Expert Opin. Investig. Drugs 2007; 16: 83-107.
10. Grothey A Galanis E. Targeting angiogenesis: progress with anti-VEGF treatment with large molecules. Nat. Rev. Clin. Oncol. 2009; 6: 507-518.
11. Ferrara N, Henzel WJ. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. 1989. Biochem. Biophys. Res. Commun. 2012; 425: 540-547.
12. Park SH, Kim BR, Lee JH, Park ST, Lee SH, Dong SM, Rho SB. GABARBP down-regulates HIF-1α expression through the VEGFR-2 and PI3K/mTOR/4E-BP1 pathways. Cell. Signal. 2014; 26: 1506-1513.
13. Carmeliet P. VEGF as a key mediator of angiogenesis in cancer. Oncology 2005; 69: 4-10.
14. Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J. Clin. Oncol. 2005; 23: 1011-1027.
15. Scott A, Mellor H. VEGF receptor trafficking in angiogenesis. Biochem. Soc. Trans. 2009; 37: 1184-1188.
16. Wang Z, Wang N, Han S, Wang D, Mo S, Yu L, Huang H, Tsui K, Shen J, Chen J. Dietary compound isoliquiritigenin inhibits breast cancer neoangiogenesis via VEGF/VEGFR-2 signaling pathway. PLoS One 2013; 8: e68566.
17. Alitalo K, Carmeliet P. Molecular mechanisms of lymphangiogenesis in health and disease. Cancer Cell 2002; 1: 219-227.
18. Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr. Rev. 2004; 25: 581-611.
19. Lee YJ, Karl DL, Maduekwe UN, Rothrock C, Ryeom S, D'Amore PA, Yoon SS. Differential effects of VEGFR-1 and VEGFR-2 inhibition on tumor metastases based on host organ environment. Cancer Res. 2010; 70: 8357-8367.
20. Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M, Wu XF, Wu XF, Breitman ML, Schuh AC. Failure of bloodisland formation and vasculogenesis in Flk-1-deficient mice. Nature 1995; 376: 62-66.
21. Haruta H, Nagata Y, Todokoro K. Role of Flk-1 in mouse hematopoietic stem cells. FEBS Lett. 2001; 507: 45-48.
22. Semenza GL. Regulation of hypoxia-induced angiogenesis: a chaperone escorts VEGF to the dance. J. Clin. Invest. 2001; 108: 39-40.
23. Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia: role of the HIF system. Nat. Med. 2003; 9: 677-684.
24. Jiang BH, Agani F, Passaniti A, Semenza GL. V-SRC induces expression of hypoxia-inducible factor 1 (HIF-1) and transcription of genes encoding vascular endothelial growth factor and enolase 1: involvement of HIF-1 in tumor progression. Cancer Res. 1997; 57: 5328-5335.
25. Carmeliet P, Dor Y, Herbert JM, Fukumura D, Brusselmans K, Dewerchin M, Neeman M, Bono F, Abramovitch R, Maxwell P, Koch CJ, Ratcliffe P, Moons L, Jain RK, Collen D, Keshert E. Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 1998; 394: 485-490.
26. Ryan HE, Lo J, Johnson RS. HIF-1 alpha is required for solid tumor formation and embryonic vascularization. EMBO J. 1998; 17: 3005-3015.
27. Halterman MW, Miller CC, Federoff HJ. Hypoxia-inducible factor-1alpha mediates hypoxia-induced delayed neuronal death that involves p53. J. Neurosci. 1999; 19: 6818-6824.
28. Harris AL. Hypoxia-a key regulatory factor in tumour growth. Nat. Rev. Cancer 2002; 2: 38-47.
29. Kunz M, Ibrahim SM. Molecular responses to hypoxia in tumor cells. Mol. Cancer 2003; 2: 23.
30. Mabjeesh NJ, Amir S. Hypoxia-inducible factor (HIF) in human tumorigenesis. Histol. Histopathol. 2007; 22: 559-572.
31. Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, Buechler P, Isaacs WB, Semenza GL, Simons JW. Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res. 1999; 59: 5830-5835.
32. Birner P, Schindl M, Obermair A, Plank C, Breitenecker G, Oberhuber G. Overexpression of hypoxia-inducible factor 1alpha is a marker for an unfavorable prognosis in earlystage invasive cervical cancer. Cancer Res. 2000; 60: 4693-4696.
33. Akakura N, Kobayashi M, Horiuchi I, Suzuki A, Wang J, Chen J, Niizeki H, Kawamura Ki, Hosokawa M, Asaka M. Constitutive expression of hypoxia-inducible factor-1alpha renders pancreatic cancer cells resistant to apoptosis induced by hypoxia and nutrient deprivation. Cancer Res. 2001; 61: 6548-6554.
34. Bos R, Zhong H, Hanrahan CF, Mommers EC, Semenza GL, Pinedo HM, Abeloff MD, Simons JW, van Diest PJ, van der Wall E. Levels of hypoxia-inducible factor-1alpha during breast carcinogenesis. J. Natl. Cancer Inst. 2001; 93: 309-314.
35. Niizeki H, Kobayashi M, Horiuchi I, Akakura N, Chen J, Wang J, Hamada JI, Seth P, Katoh H, Watanabe H, Raz A, Hosokawa M. Hypoxia enhances the expression of autocrine motility factor and the motility of human pancreatic cancer cells. Br. J. Cancer 2002; 86: 1914-1919.
36. Maxwell PH, Dachs GU, Gleadle JM, Nicholls LG, Harris AL, Stratford IJ, Hankinson O, Pugh CW, Ratcliffe PJ. Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. Proc. Natl. Acad. Sci. U S A 1997; 94: 8104-8109.
37. Fang J, Xia C, Cao Z, Zheng JZ, Reed E, Jiang BH. Apigenin inhibits VEGF and HIF-1 expression via PI3K/AKT/p70S6K1 and HDM2/p53 pathways. FASEB J. 2005; 19: 342-353.
38. Fang J, Zhou Q, Liu LZ, Xia C, Hu X, Shi X, Jiang BH. Apigenin inhibits tumor angiogenesis through decreasing HIF-1alpha and VEGF expression. Carcinogenesis 2007; 28: 858-864.
39. Hastie CJ, Vazquez-Martin C, Philp A, Stark MJ, Cohen PT. The Saccharomyces cerevisiae orthologue of the human protein phosphatase 4 core regulatory subunit R2 confers resistance to the anticancer drug cisplatin. FEBS J. 2006; 273: 3322-3334.
40. Chen GI, Tisayakorn S, Jorgensen C, D'Ambrosio LM, Goudreault M, Gingras AC. PP4R4/KIAA1622 forms a novel stable cytosolic complex with phosphoprotein phosphatase 4. J. Biol. Chem. 2008; 283: 29273-29284.
41. Chowdhury D, Xu X, Zhong X, Ahmed F, Zhong J, Liao J, Dykxhoorn DM, Weinstock DM, Pfeifer GP, Lieberman J. A PP4-phosphatase complex dephosphorylates gammaH2AX generated during DNA replication. Mol. Cell 2008; 31: 33-46.
42. Nakada S, Chen GI, Gingras AC, Durocher D. PP4 is a gamma H2AX phosphatase required for recovery from the DNA damage checkpoint. EMBO Rep. 2008; 9: 1019-1026.
43. Byun HJ, Kim BR, Yoo R, Park SY, Rho SB. sMEK1 enhances gemcitabine anti-cancer activity through inhibition of phosphorylation of Akt/mTOR. Apoptosis 2012; 17: 1095-1103.
44. Gingras AC, Caballero M, Zarske M, Sanchez A, Hazbun TR, Fields S, Sonenberg N, Hafen E, Raught B, Aebersold R. A novel, evolutionarily conserved protein phosphatase complex involved in cisplatin sensitivity. Mol. Cell. Proteomics 2005; 4: 1725-1740.
45. Zhang X, Ozawa Y, Lee H, Wen YD, Tan TH, Wadzinski BE, Seto E. Histone deacetylase 3 (HDAC3) activity is regulated by interaction with protein serine/threonine phosphatase 4. Genes Dev. 2005; 19: 827-839.
46. Mihindukulasuriya KA, Zhou G, Qin J, Tan TH. Protein phosphatase 4 interacts with and down-regulates insulin receptor substrate 4 following tumor necrosis factor-alpha stimulation. J. Biol. Chem. 2004; 279: 46588-46594.
47. Bertram PG, Choi JH, Carvalho J, Ai W, Zeng C, Chan TF, Zheng XF. Tripartite regulation of Gln3p by TOR, Ure2p, and phosphatases. J. Biol. Chem. 2000; 275: 35727-35733.
48. Yoon YS, Lee MW, Ryu D, Kim JH, Ma H, Seo WY, Kim YN, Kim SS, Lee CH, Hunter T, Choi CS, Montminy MR, Koo SH. Suppressor of MEK null (SMEK)/protein phosphatase 4 catalytic subunit (PP4C) is a key regulator of hepatic gluconeogenesis. Proc. Natl. Acad. Sci. U S A 2010; 107: 17704-17709.
49. Dong SM, Byun HJ, Kim BR, Lee SH, Trink B, Rho SB. Tumor suppressor BLU enhances pro-apoptotic activity of sMEK1 through physical interaction. Cell. Signal. 2012; 24: 1208-1214.
50. Breier G. Endothelial receptor tyrosine kinases involved in blood vessel development and tumor angiogenesis. Adv. Exp. Med. Biol. 2000; 476: 57-66.
51. Ferrara N. Role of vascular endothelial growth factor in regulation of physiological angiogenesis. Am. J. Physiol. Cell Physiol. 2001; 280: C1358-C1366.
52. Meyer RD, Rahimi N. Comparative structure-function analysis of VEGFR-1 and VEGFR-2: What have we learned from chimeric systems?. Ann. N Y Acad. Sci. 2003; 995: 200-207.
53. Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L. VEGF receptor signaling-in control of vascular function. Nat. Rev. Mol. Cell. Biol. 2006; 7: 359-371.
54. Ryan HE, Poloni M, McNulty W, Elson D, Gassmann M, Arbeit JM, Johnson RS. Hypoxia-inducible factor-1alpha is a positive factor in solid tumor growth. Cancer Res. 2000; 60: 4010-4015.
55. Ahluwalia A, Tarnawski AS. Critical role of hypoxia sensor-HIF-1alpha in VEGF gene activation. Implications for angiogenesis and tissue injury healing. Curr. Med. Chem. 2012; 19: 90-97.
56. Goetze S, Bungenstock A, Czupalla C, Eilers F, Stawowy P, Kintscher U, Spencer-Hänsch C, Graf K, Nürnberg B, Law RE, Fleck E, Gräfe M. Leptin induces endothelial cell migration through Akt, which is inhibited by PPAR gammaligands. Hypertension 2002; 40: 748-754.
57. Uruno A, Sugawara A, Kanatsuka H, Arima S, Taniyama Y, Kudo M, Takeuchi K, Ito S. Hepatocyte growth factor stimulates nitric oxide production through endothelial nitric oxide synthase activation by the phosphoinositide 3-kinase/Akt pathway and possibly by mitogen-activated protein kinase kinase in vascular endothelial cells. Hypertens. Res. 2004; 27: 887-895.
58. Semenza GL. Targeting HIF-1 for cancer therapy. Nat. Rev. Cancer 2003; 3: 721-732.
59. Fujimoto J, Sakaguchi H, Aoki I, Khatun S, Tamaya T. Clinical implications of expression of vascular endothelial growth factor in metastatic lesions of ovarian cancers. Br. J. Cancer 2001; 85: 313-316.
60. Chen H, Ye D, Xie X, Chen B, Lu W. VEGF, VEGFRs expressions and activated STATs in ovarian epithelial carcinoma. Gynecol. Oncol. 2004; 94: 630-635.
61. So J, Wang FQ, Navari J, Schreher J, Fishman DA. LPA-induced epithelial ovarian cancer (EOC) in vitro invasion and migration are mediated by VEGF receptor-2 (VEGF-R2). Gynecol. Oncol. 2005; 97: 870-878.
62. Sher I, Adham SA, Petrik J, Coomber BL. Autocrine VEGF-A/KDR loop protects epithelial ovarian carcinoma cells from anoikis. Int. J. Cancer 2009; 124: 553-561.
63. Adham SA, Sher I, Coomber BL. Molecular blockade of VEGFR2 in human epithelial ovarian carcinoma cells. Lab. Invest. 2010; 90: 709-723.
64. Yaqoob U, Cao S, Shergill U, Jagavelu K, Geng Z, Yin M, de Assuncao TM, Cao Y, Szabolcs A, Thorgeirsson S, Schwartz M, Yang JD, Ehman R, Roberts L, Mukhopadhyay D, Shah VH. Neuropilin-1 stimulates tumor growth by increasing fibronectin fibril assembly in the tumor microenvironment. Cancer Res. 2012; 72: 4047-4059.
65. Calvani M, Rapisarda A, Uranchimeg B, Shoemaker RH, Melillo G. Hypoxic induction of an HIF-1alpha-dependent bFGF autocrine loop drives angiogenesis in human endothelial cells. Blood 2006; 107: 2705-2712.
66. Mayerhofer M, Valent P, Sperr WR, Griffin JD, Sillaber C. BCR/ABL induces expression of vascular endothelial growth factor and its transcriptional activator, hypoxia inducible factor-1alpha, through a pathway involving phosphoinositide 3-kinase and the mammalian target of rapamycin. Blood 2001; 100: 3767-3775.
67. Arnal JF, Dinh-Xuan AT, Pueyo M, Darblade B, Rami J. Endothelium-derived nitric oxide and vascular physiology and pathology. Cell. Mol. Life Sci. 1999; 5: 1078-1087.
68. Jin ZG, Ueba H, Tanimoto T, Lungu AO, Frame MD, Berk BC. Ligand-independent activation of vascular endothelial growth factor receptor 2 by fluid shear stress regulates activation of endothelial nitric oxide synthase. Circ. Res. 2003; 93: 354-363.
69. Tanimoto T, Jin ZG, Berk BC. Transactivation of vascular endothelial growth factor (VEGF) receptor Flk-1/KDR is involved in sphingosine 1-phosphate-stimulated phosphorylation of Akt and endothelial nitric-oxide synthase (eNOS). J. Biol. Chem. 2002; 277: 42997-43001.
70. Michaud SE, Dussault S, Groleau J, Haddad P, Rivard A. Cigarette smoke exposure impairs VEGF-induced endothelial cell migration: role of NO and reactive oxygen species. J. Mol. Cell. Cardiol. 2006; 41: 275-284.
71. Rho SB, Lee KH, Kim JW, Shiba K, Jo YJ, Kim S. Interaction between human tRNA synthetases involves repeated sequence elements. Proc. Natl. Acad. Sci. U S A 1996; 93: 10128-10133.
72. Pang X, Yi Z, Zhang X, Sung B, Qu W, Lian X, Aggarwal BB, Liu M. Acetyl-11-keto-β-boswellic acid inhibits prostate tumor growth by suppressing vascular endothelial growth factor receptor 2-mediated angiogenesis. Cancer Res. 2009; 69: 5893-5900.
73. Saraswati S, Agrawal SS. Brucine, an indole alkaloid from strychnos nuxvomica attenuates VEGF-induced angiogenesis via inhibiting VEGFR2 signaling pathway in vitro and in vivo. Cancer Lett. 2013; 332: 83-93.
74. Rho SB, Song YJ, Lim MC, Lee SH, Kim BR, Park SY. Programmed cell death 6 (PDCD6) inhibits angiogenesis through PI3K/mTOR/p70S6K pathway by interacting of VEGFR-2. Cell. Signal. 2012; 24: 131-139.