OJCD  Vol.3 No.2 , June 2013
SCNH2 is a novel apelinergic family member acting as a potent mitogenic and chemotactic factor for both endothelial and epithelial cells
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.
Cite this paper: 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.

[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/

[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