SCNH2 is a novel apelinergic family member acting as a potent mitogenic and chemotactic factor for both endothelial and epithelial cells
Changge Fang, Ingalill Avis, Caterina Bianco, Natalie Held, Jennifer Morris, Kris Ylaya, Stephen M. Hewitt, Alfred C. Aplin, Roberto F. Nicosia, Laura A. Fung, John D. Lewis, William G. Stetler-Stevenson, David S. Salomon, Frank Cuttitta
Angiogenesis Core Facility, Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, USA.
Department of Pathology, University of Washington, Seattle, USA.
Department of Pathology, University of Washington, Seattle, USA;Pathology and Laboratory Medicine Services, Veterans Administration Puget Sound Health Care System, Seattle, USA.
Extracellular Matrix Pathology Section, Radiation Oncology Branch, Center for Cancer Research, Bethesda, USA.
Innovascreen Inc., New Glasgow, Canada.
Innovascreen Inc., New Glasgow, Canada;Department of Oncology, University of Alberta, Edmonton, Canada.
Tissue Array Research, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, USA.
Tissue Array Research, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, USA 4Department of Pathology, University of Washington, Seattle, USA.
Tumor Growth Factor Section, Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, Frederick, USA.
DOI: 10.4236/ojcd.2013.32009   PDF   HTML   XML   4,271 Downloads   6,721 Views   Citations

Abstract

The gut hormone apelin is a major therapeutic focus for several diseases involving inflammation and aberrant cell growth. We investigated whether apelin-36 contained alternative bioactive peptides associated with normal physiology or disease. Amino acid sequence analysis of apelin-36 identified an amidation motif consistent with the formation of a secondary bioactive peptide (SCNH2). SCNH2 is proven to be mitogenic and chemotactic in normal/malignant cells and augments angiogenesis via a PTX-resistant/CT-X-sensitive G protein-coupled receptor (GPCR). Notably, SCNH2 is substantially more potent and sensitive than apelin-13 and vascular endothelial growth factor-A. Endogenous SCNH2 is highly expressed in human tumors and placenta and in mouse embryonic tissues. Our findings demonstrate that SCNH2 is a new apelinergic member with critical pluripotent roles in angiogenesis related diseases and embryogenesis via a non-APJ GPCR.

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Fang, C. , Avis, I. , Bianco, C. , Held, N. , Morris, J. , Ylaya, K. , Hewitt, S. , Aplin, A. , Nicosia, R. , Fung, L. , Lewis, J. , Stetler-Stevenson, W. , Salomon, D. and Cuttitta, F. (2013) SCNH2 is a novel apelinergic family member acting as a potent mitogenic and chemotactic factor for both endothelial and epithelial cells. Open Journal of Clinical Diagnostics, 3, 37-51. doi: 10.4236/ojcd.2013.32009.

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1] Tatemoto, K., et al. (1998) Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor. Biochemical and Biophysical Research Communications, 251, 471-476. doi:10.1006/bbrc.1998.9489
[2] Falcao-Pires, I., Ladeiras-Lopes, R. and Leite-Moreira, A.F. (2010) The apelinergic system: a promising therapeutic target. Expert opinion on therapeutic targets 14, 633-645. doi:10.1517/14728221003752743
[3] Volkoff, H. and Wyatt, J.L. (2009) Apelin in goldfish (Carassius auratus): Cloning, distribution and role in appetite regulation. Peptides, 30, 1434-1440. doi:10.1016/j.peptides.2009.04.020
[4] Wang, G., et al. (2004) Apelin, a new enteric peptide: Localization in the gastrointestinal tract, ontogeny, and stimulation of gastric cell proliferation and of cholecystokinin secretion. Endocrinology, 145, 1342-1348. doi:10.1210/en.2003-1116
[5] Han, S., Wang, G., Qi, X., Lee, H.M., Englander, E.W. and Greeley Jr., G.H. (2008) A possible role for hypoxia-induced apelin expression in enteric cell proliferation. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, 294, R1832-1839. doi:10.1152/ajpregu.00083.2008
[6] Eyries, M., Siegfried, G., Ciumas, M., Montagne, K., Agrapart, M., Lebrin, F. and Soubrier, F. (2008) Hypoxia-induced apelin expression regulates endothelial cell proliferation and regenerative angiogenesis. Circulation Research, 103, 432-440. doi:10.1161/CIRCRESAHA.108.179333
[7] Del Toro, R., et al. (2010) Identification and functional analysis of endothelial tip cell-enriched genes. Blood, 116, 4025-4033. doi:10.1182/blood-2010-02-270819
[8] Kidoya, H., Kunii, N., Naito, H., Muramatsu, F., Okamoto, Y., Nakayama, T. and Takakura, N. (2011) The apelin/APJ system induces maturation of the tumor vasculature and improves the efficiency of immune therapy. Oncogene, 31, 3254-3264.
[9] Tatemoto, K. and Mutt, V. (1980) Isolation of two novel candidate hormones using a chemical method for finding naturally occurring polypeptides. Nature, 285, 417-418. doi:10.1038/285417a0
[10] Siegfried, J.M., Kasprzyk, P.G., Treston, A.M., Mulshine, J.L., Quinn, K.A. and Cuttitta, F. (1992) A mitogenic peptide amide encoded within the E peptide domain of the insulin-like growth factor IB prohormone. Proceedings of the National Academy of Sciences of the United States of America, 89, 8107-8111. doi:10.1073/pnas.89.17.8107
[11] Cuttitta, F. (1993) Peptide amidation: Signature of bioactivity. The Anatomical Record, 236, 87-93, 172-173. doi:10.1002/ar.1092360112
[12] Eguchi, S., et al. (1994) Structure-activity relationship of adrenomedullin, a novel vasodilatory peptide, in cultured rat vascular smooth muscle cells. Endocrinology, 135, 2454-2458. doi:10.1210/en.135.6.2454
[13] Kitamura, K., Kato, J., Kawamoto, M., Tanaka, M., Chino, N., Kangawa, K. and Eto, T. (1998) The intermediate form of glycine-extended adrenomedullin is the major circulating molecular form in human plasma. Biochemical and Biophysical Research Communications, 244, 551-555. doi:10.1006/bbrc.1998.8310
[14] Cornish, J., Callon, K.E., Coy, D.H., Jiang, N.Y., Xiao, L., Cooper, G.J. and Reid, I.R. (1997) Adrenomedullin is a potent stimulator of osteoblastic activity in vitro and in vivo. The American Journal of Physiology, 273, E1113-E1120.
[15] Shichiri, M., Fukai, N., Ozawa, N., Iwasaki, H. and Hirata, Y. (2003) Adrenomedullin is an autocrine/paracrine growth factor for rat vascular smooth muscle cells. Regulatory Peptides, 112, 167-173. doi:10.1016/S0167-0115(03)00036-3
[16] Martinez, A., Miller, M.J., Unsworth, E.J., Siegfried, J.M. and Cuttitta, F. (1995) Expression of adrenomedullin in normal human lung and in pulmonary tumors. Endocrinology, 136, 4099-4105. doi:10.1210/en.136.9.4099
[17] Bianco, C., et al. (2005) Role of human cripto-1 in tumor angiogenesis. Journal of the National Cancer Institute, 97, 132-141. doi:10.1093/jnci/dji011
[18] Chaturvedi, K. and Sarkar, D.K. (2005) Role of protein kinase C-Ras-MAPK p44/42 in ethanol and transforming growth factor-beta3-induced basic fibroblast growth factor release from folliculostellate cells. The Journal of Pharmacology and Experimental Therapeutics, 314, 1346-1352. doi:10.1124/jpet.105.088302
[19] Masri, B., Lahlou, H., Mazarguil, H., Knibiehler, B. and Audigier, Y. (2002) Apelin (65-77) activates extracellular signal-regulated kinases via a PTX-sensitive G protein. Biochemical and Biophysical Research Communications, 290, 539-545. doi:10.1006/bbrc.2001.6230
[20] Aplin, A.C., Fogel, E., Zorzi, P. and Nicosia, R.F. (2008) The aortic ring model of angiogenesis. Methods in Enzymology, 443, 119-136. doi:10.1016/S0076-6879(08)02007-7
[21] Zijlstra, A., Seandel, M., Kupriyanova, T.A., Partridge, J.J., Madsen, M.A., Hahn-Dantona, E.A., Quigley, J.P. and Deryugina, E.I. (2006) Proangiogenic role of neutrophil-like inflammatory heterophils during neovascularization induced by growth factors and human tumor cells. Blood, 107, 317-327. doi:10.1182/blood-2005-04-1458
[22] Dokholyan, N.V. and Shakhnovich, E.I. (2001) Understanding hierarchical protein evolution from first principles. Journal of Molecular Biology, 312, 289-307. doi:10.1006/jmbi.2001.4949
[23] Greten, F.R., Eckmann, L., Greten, T.F., Park, J.M., Li, Z.W., Egan, L.J., Kagnoff, M.F. and Karin, M. (2004) IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell, 118, 285-296. doi:10.1016/j.cell.2004.07.013
[24] Folkman, J. (1971) Tumor angiogenesis: Therapeutic implications. The New England Journal of Medicine, 285, 1182-1186. doi:10.1056/NEJM197111182852108
[25] Nanus, D.M., Schmitz-Drager, B.J., Motzer, R.J., Lee, A.C., Vlamis, V., Cordon-Cardo, C., Albino, A.P. and Reuter, V.E. (1993) Expression of basic fibroblast growth factor in primary human renal tumors: Correlation with poor survival. Journal of the National Cancer Institute, 85, 1597-1599. doi:10.1093/jnci/85.19.1597
[26] Tang, S.Y., et al. (2007) Apelin stimulates proliferation and suppresses apoptosis of mouse osteoblastic cell line MC3T3-E1 via JNK and PI3-K/Akt signaling pathways. Peptides, 28, 708-718. doi:10.1016/j.peptides.2006.10.005
[27] Simpkin, J.C., Yellon, D.M., Davidson, S.M., Lim, S.Y., Wynne, A.M. and Smith, C.C. (2007) Apelin-13 and apelin-36 exhibit direct cardioprotective activity against ischemia-reperfusion injury. Basic Research in Cardiology, 102, 518-528. doi:10.1007/s00395-007-0671-2
[28] Fields, T.A. and Casey, P.J. (1997) Signalling functions and biochemical properties of pertussis toxin-resistant G-proteins. The Biochemical Journal, 321, 561-571.
[29] Gilman, A.G. (1987) G proteins: Transducers of receptor-generated signals. Annual Review of Biochemistry, 56, 615-649. doi:10.1146/annurev.bi.56.070187.003151
[30] Goode, T.L. and Raffa, R.B. (1997) An examination of the relationship between mu-opioid antinociceptive efficacy and G-protein coupling using pertussis and cholera toxins. Life Sciences, 60, PL107-113. doi:10.1016/S0024-3205(96)00684-4
[31] Naruse, K., Innes, B.A., Bulmer, J.N., Robson, S.C., Searle, R.F. and Lash, G.E. (2010) Secretion of cytokines by villous cytotrophoblast and extravillous trophoblast in the first trimester of human pregnancy. Journal of Reproductive Immunology, 86, 148-150. doi:10.1016/j.jri.2010.04.004
[32] Plaisier, M. (2011) Decidualisation and angiogenesis. Best practice & research. Clinical Obstetrics & Gynaecology, 25, 259-271. doi:10.1016/j.bpobgyn.2010.10.011
[33] Yotsumoto, S., Shimada, T., Cui, C.Y., Nakashima, H., Fujiwara, H. and Ko, M.S. (1998) Expression of adrenomedullin, a hypotensive peptide, in the trophoblast giant cells at the embryo implantation site in mouse. Developmental Biology, 203, 264-275. doi:10.1006/dbio.1998.9073
[34] Montuenga, L.M., Martinez, A., Miller, M.J., Unsworth, E.J. and Cuttitta, F. (1997) Expression of adrenomedullin and its receptor during embryogenesis suggests autocrine or paracrine modes of action. Endocrinology, 138, 440-451. doi:10.1210/en.138.1.440
[35] Zhang, J., Zheng, M., Eipper, B.A. and Pintar, J.E. (1997) Embryonic and uterine expression patterns of peptidylglycine alpha-amidating monooxygenase transcripts suggest a widespread role for amidated peptides in development. Developmental Biology, 192, 375-391. doi:10.1006/dbio.1997.8750
[36] Berta, J., et al. (2010) Apelin expression in human non-small cell lung cancer: Role in angiogenesis and prognosis. Journal of Thoracic Oncology: Official Publication of the International Association for the Study of Lung Cancer, 5, 1120-1129.
[37] Heo, K., et al. (2012) Hypoxia-induced up-regulation of apelin is associated with a poor prognosis in oral squamous cell carcinoma patients. Oral Oncology, 48, 500-5006. doi:10.1016/j.oraloncology.2011.12.015

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