The HGR motif is the antiangiogenic determinant of vasoinhibin: implications for a therapeutic orally active oligopeptide
Tóm tắt
The hormone prolactin acquires antiangiogenic and antivasopermeability properties after undergoing proteolytic cleavage to vasoinhibin, an endogenous prolactin fragment of 123 or more amino acids that inhibits the action of multiple proangiogenic factors. Preclinical and clinical evidence supports the therapeutic potential of vasoinhibin against angiogenesis-related diseases including diabetic retinopathy, peripartum cardiomyopathy, rheumatoid arthritis, and cancer. However, the use of vasoinhibin in the clinic has been limited by difficulties in its production. Here, we removed this barrier to using vasoinhibin as a therapeutic agent by showing that a short linear motif of just three residues (His46-Gly47-Arg48) (HGR) is the functional determinant of vasoinhibin. The HGR motif is conserved throughout evolution, its mutation led to vasoinhibin loss of function, and oligopeptides containing this sequence inhibited angiogenesis and vasopermeability with the same potency as whole vasoinhibin. Furthermore, the oral administration of an optimized cyclic retro-inverse vasoinhibin heptapeptide containing HGR inhibited melanoma tumor growth and vascularization in mice and exhibited equal or higher antiangiogenic potency than other antiangiogenic molecules currently used as anti-cancer drugs in the clinic. Finally, by unveiling the mechanism that obscures the HGR motif in prolactin, we anticipate the development of vasoinhibin-specific antibodies to solve the on-going challenge of measuring endogenous vasoinhibin levels for diagnostic and interventional purposes, the design of vasoinhibin antagonists for managing insufficient angiogenesis, and the identification of putative therapeutic proteins containing HGR.
Tài liệu tham khảo
Carmeliet P (2003) Angiogenesis in health and disease. Nat Med 9:653–660. https://doi.org/10.1038/nm0603-653
Jayson GC, Kerbel R, Ellis LM, Harris AL (2016) Antiangiogenic therapy in oncology: current status and future directions. Lancet 388:518–529. https://doi.org/10.1016/S0140-6736(15)01088-0
Apte RS, Chen DS, Ferrara N (2019) VEGF in signaling and disease: beyond discovery and development. Cell 176:1248–1264. https://doi.org/10.1016/j.cell.2019.01.021
Fallah A, Sadeghinia A, Kahroba H et al (2019) Therapeutic targeting of angiogenesis molecular pathways in angiogenesis-dependent diseases. Biomed Pharmacother 110:775–785. https://doi.org/10.1016/j.biopha.2018.12.022
Qin S, Li A, Yi M et al (2019) Recent advances on anti-angiogenesis receptor tyrosine kinase inhibitors in cancer therapy. J Hematol Oncol 12:27. https://doi.org/10.1186/s13045-019-0718-5
Bergers G, Hanahan D (2008) Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8:592–603. https://doi.org/10.1038/nrc2442
Xu H, Zhao G, Yang J, Wen X (2019) Advances in toxicity risk analysis and effective treatments for targeted antiangiogenic drugs. Int J Clin Exp Med 12:12020–12027
Rao N, Lee YF, Ge R (2015) Novel endogenous angiogenesis inhibitors and their therapeutic potential. Acta Pharmacol Sin 36:1177–1190. https://doi.org/10.1038/aps.2015.73
Nyberg P, Xie L, Kalluri R (2005) Endogenous inhibitors of angiogenesis. Cancer Res 65:3967–3979. https://doi.org/10.1158/0008-5472.CAN-04-2427
Cao Y (2001) Endogenous angiogenesis inhibitors and their therapeutic implications. Int J Biochem Cell Biol 33:357–369. https://doi.org/10.1016/s1357-2725(01)00023-1
Rosca EV, Koskimaki JE, Rivera CG et al (2011) Anti-angiogenic peptides for cancer therapeutics. Curr Pharm Biotechnol 12:1101–1116. https://doi.org/10.2174/138920111796117300
Lau JL, Dunn MK (2018) Therapeutic peptides: historical perspectives, current development trends, and future directions. Bioorg Med Chem 26:2700–2707. https://doi.org/10.1016/j.bmc.2017.06.052
Clapp C, Thebault S, Jeziorski MC, Martínez De La Escalera G (2009) Peptide hormone regulation of angiogenesis. Physiol Rev 89:1177–1215. https://doi.org/10.1152/physrev.00024.2009
Clapp C, Thebault S, Macotela Y et al (2015) Regulation of blood vessels by prolactin and vasoinhibins. Adv Exp Med Biol 846:83–95. https://doi.org/10.1007/978-3-319-12114-7_4
Bajou K, Herkenne S, Thijssen VL et al (2014) PAI-1 mediates the antiangiogenic and profibrinolytic effects of 16K prolactin. Nat Med 20:741–747. https://doi.org/10.1038/nm.3552
Triebel J, Bertsch T, Bollheimer C et al (2015) Principles of the prolactin/vasoinhibin axis. Am J Physiol Regul Integr Comp Physiol ajpregu 00256:2015. https://doi.org/10.1152/ajpregu.00256.2015
Triebel J, Macotela Y, de la Escalera GM, Clapp C (2011) Prolactin and vasoinhibins: endogenous players in diabetic retinopathy. IUBMB Life 63:806–810. https://doi.org/10.1002/iub.518
Nuñez-Amaro CD, Moreno-Vega AI, Adan-Castro E et al (2020) Levosulpiride increases the levels of prolactin and antiangiogenic vasoinhibin in the vitreous of patients with proliferative diabetic retinopathy. Transl Vis Sci Technol 9:27–27. https://doi.org/10.1167/tvst.9.9.27
Zepeda-Romero LC, Vazquez-Membrillo M, Adan-Castro E et al (2017) Higher prolactin and vasoinhibin serum levels associated with incidence and progression of retinopathy of prematurity. Pediatr Res 81:473–479. https://doi.org/10.1038/pr.2016.241
Hilfiker-Kleiner D, Kaminski K, Podewski E et al (2007) A cathepsin D-cleaved 16 kDa form of prolactin mediates postpartum cardiomyopathy. Cell 128:589–600. https://doi.org/10.1016/j.cell.2006.12.036
Gonzalez C, Parra A, Ramirez-Peredo J et al (2007) Elevated vasoinhibins may contribute to endothelial cell dysfunction and low birth weight in preeclampsia. Lab Invest 87:1009–1017. https://doi.org/10.1038/labinvest.3700662
Ortiz G, Ledesma-Colunga MG, Wu Z et al (2020) Vasoinhibin reduces joint inflammation, bone loss, and the angiogenesis and vasopermeability of the pannus in murine antigen-induced arthritis. Lab Invest 100:1068–1079. https://doi.org/10.1038/s41374-020-0432-5
Moreno-Carranza B, Robles JP, Cruces-Solís H et al (2019) Sequence optimization and glycosylation of vasoinhibin: pitfalls of recombinant production. Protein Expr Purif 161:49–56. https://doi.org/10.1016/j.pep.2019.04.011
Clapp C, Aranda J, Gonzalez C et al (2006) Vasoinhibins: endogenous regulators of angiogenesis and vascular function. Trends Endocrinol Metab 17:301–307. https://doi.org/10.1016/j.tem.2006.08.002
Robles JP, Zamora M, Velasco-Bolom JL et al (2018) Vasoinhibin comprises a three-helix bundle and its antiangiogenic domain is located within the first 79 residues. Sci Rep 8:17111. https://doi.org/10.1038/s41598-018-35383-7
Lee J, Majumder S, Chatterjee S, Muralidhar K (2011) Inhibitory activity of the peptides derived from buffalo prolactin on angiogenesis. J Biosci 36:341–354
Galfione M, Luo W, Kim J et al (2003) Expression and purification of the angiogenesis inhibitor 16-kDa prolactin fragment from insect cells. Protein Expr Purif 28:252–258
Keeler C, Dannies PS, Hodsdon ME (2003) The tertiary structure and backbone dynamics of human prolactin. J Mol Biol 328:1105–1121. https://doi.org/10.1016/s0022-2836(03)00367-x
Van Der Spoel D, Lindahl E, Hess B et al (2005) GROMACS: fast, flexible, and free. J Comput Chem 26:1701–1718. https://doi.org/10.1002/jcc.20291
Teilum K, Hoch JC, Goffin V et al (2005) Solution structure of human prolactin. J Mol Biol 351:810–823. https://doi.org/10.1016/j.jmb.2005.06.042
Baudin B, Bruneel A, Bosselut N, Vaubourdolle M (2007) A protocol for isolation and culture of human umbilical vein endothelial cells. Nat Protoc 2:481–485. https://doi.org/10.1038/nprot.2007.54
Salic A, Mitchison TJ (2008) A chemical method for fast and sensitive detection of DNA synthesis in vivo. Proc Natl Acad Sci U S A 105:2415–2420. https://doi.org/10.1073/pnas.0712168105
Liang CC, Park AY, Guan JL (2007) In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro. Nat Protoc 2:329–333. https://doi.org/10.1038/nprot.2007.30
Carpenter AE, Jones TR, Lamprecht MR et al (2006) Cell Profiler: image analysis software for identifying and quantifying cell phenotypes. Genome Biol 7:R100. https://doi.org/10.1186/gb-2006-7-10-r100
Justus CR, Leffler N, Ruiz-Echevarria M, Yang LV (2014) In vitro cell migration and invasion assays. J Vis Exp 88:51046. https://doi.org/10.3791/51046
Brown RM, Meah CJ, Heath VL et al (2016) Tube-forming assays. In: Martin SG, Hewett PW (eds) Angiogenesis protocols. Springer, New York, pp 149–157
Carpentier G, Berndt S, Ferratge S et al (2020) Angiogenesis analyzer for ImageJ—a comparative morphometric analysis of “Endothelial Tube Formation Assay” and “Fibrin Bead Assay.” Sci Rep 10:11568. https://doi.org/10.1038/s41598-020-67289-8
Malinda KM (2009) In vivo matrigel migration and angiogenesis assay. In: Murray C, Martin S (eds) Angiogenesis protocols, 2nd edn. Humana Press, Totowa, pp 287–294
Coltrini D, Di Salle E, Ronca R et al (2013) Matrigel plug assay: evaluation of the angiogenic response by reverse transcription-quantitative PCR. Angiogenesis 16:469–477. https://doi.org/10.1007/s10456-012-9324-7
Vázquez-Membrillo M, Siqueiros-Márquez L, Núñez FF et al (2020) Prolactin stimulates the vascularization of the retina in newborn mice under hyperoxia conditions. J Neuroendocrinol 32:e12858. https://doi.org/10.1111/jne.12858
Ramírez M, Wu Z, Moreno-Carranza B et al (2011) Vasoinhibin gene transfer by adenoassociated virus type 2 protects against VEGF- and diabetes-induced retinal vasopermeability. Invest Ophthalmol Vis Sci 52:8944–8950. https://doi.org/10.1167/iovs.11-8190
Nguyen NQ, Cornet A, Blacher S et al (2007) Inhibition of tumor growth and metastasis establishment by adenovirus-mediated gene transfer delivery of the antiangiogenic factor 16K hPRL. Mol Ther 15:2094–2100. https://doi.org/10.1038/sj.mt.6300294
Struman I, Bentzien F, Lee H et al (1999) Opposing actions of intact and N-terminal fragments of the human prolactin/growth hormone family members on angiogenesis: an efficient mechanism for the regulation of angiogenesis. Proc Natl Acad Sci U S A 96:1246–1251
Stahl A, Connor KM, Sapieha P et al (2010) The mouse retina as an angiogenesis model. Invest Ophthalmol Vis Sci 51:2813–2826. https://doi.org/10.1167/iovs.10-5176
Arredondo Zamarripa D, Diaz-Lezama N, Melendez Garcia R et al (2014) Vasoinhibins regulate the inner and outer blood-retinal barrier and limit retinal oxidative stress. Front Cell Neurosci 8:333. https://doi.org/10.3389/fncel.2014.00333
Garcia C, Aranda J, Arnold E et al (2008) Vasoinhibins prevent retinal vasopermeability associated with diabetic retinopathy in rats via protein phosphatase 2A-dependent eNOS inactivation. J Clin Invest 118:2291–2300. https://doi.org/10.1172/JCI34508
Nielsen DS, Shepherd NE, Xu W et al (2017) Orally absorbed cyclic peptides. Chem Rev 117:8094–8128. https://doi.org/10.1021/acs.chemrev.6b00838
Bentzien F, Struman I, Martini JF et al (2001) Expression of the antiangiogenic factor 16K hPRL in human HCT116 colon cancer cells inhibits tumor growth in Rag1(-/-) mice. Cancer Res 61:7356–7362
Kim J, Luo W, Chen DT et al (2003) Antitumor activity of the 16-kDa prolactin fragment in prostate cancer. Cancer Res 63:386–393
Haas NB, Manola J, Uzzo RG et al (2016) Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet 387:2008–2016. https://doi.org/10.1016/S0140-6736(16)00559-6
Nguyen N-Q-N, Tabruyn SP, Lins L et al (2006) Prolactin/growth hormone-derived antiangiogenic peptides highlight a potential role of tilted peptides in angiogenesis. Proc Natl Acad Sci USA 103:14319–14324. https://doi.org/10.1073/pnas.0606638103
Clapp C, Martínez de la Escalera L, Martínez de la Escalera G (2012) Prolactin and blood vessels: a comparative endocrinology perspective. Gen Comp Endocrinol 176:336–340. https://doi.org/10.1016/j.ygcen.2011.12.033
Neduva V, Russell RB (2005) Linear motifs: evolutionary interaction switches. FEBS Lett 579:3342–3345. https://doi.org/10.1016/j.febslet.2005.04.005
Lyon KF, Cai X, Young RJ et al (2018) Minimotif Miner 4: a million peptide minimotifs and counting. Nucleic Acids Res 46:D465–D470. https://doi.org/10.1093/nar/gkx1085
Karagiannis ED, Popel AS (2008) A systematic methodology for proteome-wide identification of peptides inhibiting the proliferation and migration of endothelial cells. Proc Natl Acad Sci USA 105:13775. https://doi.org/10.1073/pnas.0803241105
Blanco JL, Porto-Pazos AB, Pazos A, Fernandez-Lozano C (2018) Prediction of high anti-angiogenic activity peptides in silico using a generalized linear model and feature selection. Sci Rep 8:15688. https://doi.org/10.1038/s41598-018-33911-z
Aykul S, Martinez-Hackert E (2016) Determination of half-maximal inhibitory concentration using biosensor-based protein interaction analysis. Anal Biochem 508:97–103. https://doi.org/10.1016/j.ab.2016.06.025
Hilfiker-Kleiner D, Haghikia A, Berliner D et al (2017) Bromocriptine for the treatment of peripartum cardiomyopathy: a multicentre randomized study. Eur Heart J 38:2671–2679. https://doi.org/10.1093/eurheartj/ehx355
Robles-Osorio ML, García-Franco R, Núñez-Amaro CD et al (2018) Basis and design of a randomized clinical trial to evaluate the effect of levosulpiride on retinal alterations in patients with diabetic retinopathy and diabetic macular edema. Front Endocrinol (Lausanne) 9:242. https://doi.org/10.3389/fendo.2018.00242