Ferdowsi University of Mashhad

Document Type : Research Articles


Department of Molecular and Cell Biology, Faculty of Basic Sciences, University of Mazandaran, Babolsar, Iran


     In this study, putative interactions between all of the retinoic acid (RA) ligands (all-trans (At), 9-cis (9c), and 13-cis (13c)), and VEGF receptors (VEGFR-1, -2 and -3) were investigated. It was performed considering the glycosylation status of the receptors to achieve a more reliable mode of interactions based on glycomics. We found that RAs may have a higher affinity for ligand-binding domains in VEGFRs. Furthermore, all RA isomers can strongly attach to VEGFR-3 receptor in comparison to other ones. It was also demonstrated that receptor dimerization of RAs may be less targeted. Moreover, regarding post-translational modifications, glycosylated structures showed conflicting binding energies. RAs may target the human vasculature, specifically lymph vessels, through VEGFR-3. In addition, the ligand binding-mediated activation of VEGFRs may be affected by these agents. Also, the glycosylation status of the receptors can interfere with these manners. Furthermore, our results confirmed that the consideration of carbohydrates in crystal structures is essential for a better interpretation of ligand/receptor interactions during drug discovery studies. Even though these observations improved our understanding of the binding patterns of RAs to VEGFRs, validation of these results needs further analysis to introduce these biomolecules as anti-VEGF remedies.


Aizpurua-Olaizola O., Toraño J.S., Falcon-Perez J.M., Williams C., Reichardt N. and Boons G-J. (2018) Mass spectrometry for glycan biomarker discovery. TrAC Trends in Analytical Chemistry 100: 7-14.
Albini A., Tosetti F., Li V.W., Noonan D.M. and Li W.W. (2012) Cancer prevention by targeting angiogenesis. Nature reviews Clinical oncology 9(9): 498.
Álvarez-Aznar A., Muhl L. and Gaengel K. (2017) VEGF receptor tyrosine kinases: key regulators of vascular function. In Current topics in developmental biology (Vol. 123: pp. 433-482): Elsevier.
Applegate C.C. and Lane M.A. (2015) Role of retinoids in the prevention and treatment of colorectal cancer. World journal of gastrointestinal oncology 7(10): 184.
Christensen S.T., Morthorst S.K., Mogensen J.B. and Pedersen L.B. (2017) Primary cilia and coordination of receptor tyrosine kinase (RTK) and transforming growth factor β (TGF-β) signaling. Cold Spring Harbor perspectives in biology 9(6): a028167.
Contessa J.N., Bhojani M.S., Freeze H.H., Ross B.D., Rehemtulla A. and Lawrence T.S. (2010) Molecular imaging of N-linked glycosylation suggests glycan biosynthesis is a novel target for cancer therapy. Clinical Cancer Research 16(12): 3205-3214.
Costantini L., Molinari R., Farinon B., and Merendino N. (2020) Retinoic acids in the treatment of most lethal solid cancers. Journal of clinical medicine 9(2): 360.
Di Masi A., Leboffe L., De Marinis E., Pagano F., Cicconi L., Rochette-Egly C. and et al. (2015) Retinoic acid receptors: from molecular mechanisms to cancer therapy. Molecular aspects of medicine 41: 1-115.
Dunning M.W. (2018) Quantification and Profiling of Hepatic Retinoid in Freshwater Fishes by Liquid Chromatography–Tandem Mass Spectrometry (Master's thesis, University of Waterloo).
Goel H.L. and Mercurio A.M. (2013) VEGF targets the tumour cell. Nature Reviews Cancer 13(12): 871-882.
Gomes Ferreira I., Pucci M., Venturi G., Malagolini N., Chiricolo M. and Dall’Olio F. (2018) Glycosylation as a main regulator of growth and death factor receptors signaling. International journal of molecular sciences 19(2): 580.
Greenberg J.I., Shields D.J., Barillas S.G., Acevedo L.M., Murphy E., Huang J. and et al. (2008) A role for VEGF as a negative regulator of pericyte function and vessel maturation. Nature 456(7223): 809-813.
Gudas L.J. (1994) Retinoids and vertebrate development. Journal of Biological Chemistry 269(22): 15399-15402.
Guex N., Peitsch M.C. and Schwede T. (2009) Automated comparative protein structure modeling with SWISS‐MODEL and Swiss‐PdbViewer: A historical perspective. Electrophoresis 30(S1): S162-S173.
Hegde P.S., Wallin J.J. and Mancao C. (2018) Predictive markers of anti-VEGF and emerging role of angiogenesis inhibitors as immunotherapeutics. Paper presented at the Seminars in cancer biology.
Huang M., Ye Y-c., Chen S., Chai J-R., Lu J-X., Gu L-J. and Wang Z-Y. (1988) Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia.
Hu P., van Dam A. M., Wang Y., Lucassen P. J. and Zhou J. N. (2020) Retinoic acid and depressive disorders: Evidence and possible neurobiological mechanisms. Neuroscience & Biobehavioral Reviews 112: 376-391.
Itkonen H.M. and Mills I.G. (2013) N-linked glycosylation supports cross-talk between receptor tyrosine kinases and androgen receptor. PloS one 8(5).
Jeltsch M., Karpanen T., Strandin T., Aho K., Lankinen H. and Alitalo K. (2006) Vascular endothelial growth factor (VEGF)/VEGF-C mosaic molecules reveal specificity determinants and feature novel receptor binding patterns. Journal of Biological Chemistry 281(17): 12187-12195.
Khalil S., Bardawil T., Stephan C., Darwiche N., Abbas O., Kibbi A.G. and et al. (2017) Retinoids: a journey from the molecular structures and mechanisms of action to clinical uses in dermatology and adverse effects. Journal of Dermatological Treatment 28(8): 684-696.
Lee J.M., Cimino-Mathews A., Peer C.J., Zimmer A., Lipkowitz S., Annunziata C.M. and et al. (2017) Safety and clinical activity of the programmed death-ligand 1 inhibitor durvalumab in combination with poly (ADP-ribose) polymerase inhibitor olaparib or vascular endothelial growth factor receptor 1-3 inhibitor cediranib in women's cancers: a dose-escalation, phase I study. Journal of Clinical Oncology 35(19): 2193.
Leppänen V.M., Prota A.E., Jeltsch M., Anisimov A., Kalkkinen N., Strandin T. et al. (2010) Structural determinants of growth factor binding and specificity by VEGF receptor 2. Proceedings of the National Academy of Sciences 107(6): 2425-2430.
Leppänen V.M., Tvorogov D., Kisko K., Prota A.E., Jeltsch M., Anisimov A. and et al. (2013) Structural and mechanistic insights into VEGF receptor 3 ligand binding and activation. Proceedings of the National Academy of Sciences 110(32): 12960-12965.
Liu X., Wu J., Wang J., Liu X., Zhao S., Li Z. and et al. (2009) WebLab: a data-centric, knowledge-sharing bioinformatic platform. Nucleic acids research 37(suppl_2): W33-W39.
Lodi G., Franchini R., Warnakulasuriya S., Varoni E.M., Sardella A., Kerr A.R. et al. (2016) Interventions for treating oral leukoplakia to prevent oral cancer. Cochrane Database of Systematic Reviews(7).
Lopez-Sambrooks C., Shrimal S., Khodier C., Flaherty D.P., Rinis N., Charest J.C. and et al. (2016) Oligosaccharyltransferase inhibition induces senescence in RTK-driven tumor cells. Nature chemical biology 12(12): 1023.
Ma X. and Ning S. (2019) Cyanidin‐3‐glucoside attenuates the angiogenesis of breast cancer via inhibiting STAT3/VEGF pathway. Phytotherapy research 33(1): 81-89.
Mallipattu S.K. and He J.C. (2015) The beneficial role of retinoids in glomerular disease. Frontiers in medicine 2, 16.
Markovic-Mueller S., Stuttfeld E., Asthana M., Weinert T., Bliven S., Goldie K.N. and et al. (2017) Structure of the Full-length VEGFR-1 Extracellular Domain in Complex with VEGF-A. Structure 25(2): 341-352.
Mercer A.A., Wise L.M., Scagliarini A., McInnes C.J., Büttner M., Rziha H.J. and et al. (2002) Vascular endothelial growth factors encoded by Orf virus show surprising sequence variation but have a conserved, functionally relevant structure. Journal of General Virology 83(11): 2845-2855.
Minkina A., Lindeman R.E., Gearhart M.D., Chassot A.A., Chaboissier M.C., Ghyselinck N.B. and et al. (2017) Retinoic acid signaling is dispensable for somatic development and function in the mammalian ovary. Developmental biology 424(2): 208-220.
Moon T.E., Levine N., Cartmel B., Bangert J.L., Rodney S., Dong Q. and et al. (1997) Effect of retinol in preventing squamous cell skin cancer in moderate-risk subjects: a randomized, double-blind, controlled trial. Southwest Skin Cancer Prevention Study Group. Cancer Epidemiology and Prevention Biomarkers 6(11): 949-956.
Njar V., Mbatia H., Ramamurthy V. and Ramalingam S. (2019) 13-Cis-Ramba Retinamides That Degrade Mnks For Treating Cancer. In: Google Patents.
Noonan D.M., Benelli R. and Albini A. (2007) Angiogenesis and cancer prevention: a vision. In Cancer Prevention (pp. 219-224): Springer.
Pourhashem Z., Mehrpouya M., Yardehnavi N., Eslamparast A. and Kazemi-Lomedasht F. (2017). An in-silico approach to find a peptidomimetic targeting extracellular domain of HER3 from a HER3 Nanobody. Computational biology and chemistry 68: 39-42.
Qiao J., Huang F., Naikawadi R.P., Kim K.S., Said T. and Lum H. (2006) Lysophosphatidylcholine impairs endothelial barrier function through the G protein-coupled receptor GPR4. American Journal of Physiology-Lung Cellular and Molecular Physiology 291(1): L91-L101.
Reid C.W., Twine S.M., and Reid AN. (2012) Bacterial glycomics: current research, technology and applications: Caister Academic Press.
Roudini L., NayebZadeh Eidgahi N., Rahimi H. R., Saberi M. R., Amiri Tehranizadeh Z., Beigoli S. and et al. (2020) Determining the interaction behavior of calf thymus DNA with berberine hydrochloride in the presence of linker histone: a biophysical study. Journal of Biomolecular Structure and Dynamics 38(2): 364-381.
Rönn R.E., Guibentif C., Moraghebi R., Chaves P., Saxena S., Garcia B. and Woods N-B. (2015) Retinoic acid regulates hematopoietic development from human pluripotent stem cells. Stem Cell Reports 4(2): 269-281.
Rudd P., Karlsson N.G., Khoo K-H. and Packer N.H. (2017) Glycomics and glycoproteomics. In Essentials of Glycobiology [Internet]. 3rd edition: Cold Spring Harbor Laboratory Press.
Rühl R., Krężel W. & de Lera A.R. (2018) 9-Cis-13, 14-dihydroretinoic acid, a new endogenous mammalian ligand of retinoid X receptor and the active ligand of a potential new vitamin A category: vitamin A5. Nutrition reviews 76(12): 929-941.
Shibuya M. (2013) VEGFR and type-V RTK activation and signaling. Cold Spring Harbor perspectives in biology 5(10): a009092.
Simandi Z., Horvath A., Cuaranta-Monroy I., Sauer S., Deleuze J-F. and Nagy L. (2018) RXR heterodimers orchestrate transcriptional control of neurogenesis and cell fate specification. Molecular and cellular endocrinology 471: 51-62.
Stuttfeld E. and Ballmer‐Hofer K. (2009) Structure and function of VEGF receptors. IUBMB life 61(9): 915-922.
Szymański Ł., Skopek R., Palusińska M., Schenk T., Stengel S., Lewicki S. ... and Zelent A. (2020) Retinoic Acid and Its Derivatives in Skin. Cells 9(12): 2660.
Tarapcsák S., Szalóki G., Telbisz Á., Gyöngy Z., Matúz K., Csősz É., Nagy P., Holb I.J., Rühl R., Nagy L. and Szabó G. (2017) Interactions of retinoids with the ABC transporters P-glycoprotein and Breast Cancer Resistance Protein. Scientific reports 7(1): 1-11.
Tsuji M., Shudo K. and Kagechika H. (2015) Docking simulations suggest that all-trans retinoic acid could bind to retinoid X receptors. Journal of computer-aided molecular design 29(10): 975-988.
Uray I.P., Dmitrovsky E. and Brown P.H. (2016) Retinoids and rexinoids in cancer prevention: from laboratory to clinic. Paper presented at the Seminars in oncology.
Urushitani H., Katsu Y., Kagechika H., Sousa A.C., Barroso C.M., Ohta Y. and et al. (2018) Characterization and comparison of transcriptional activities of the retinoid X receptors by various organotin compounds in three prosobranch gastropods; Thais clavigera, Nucella lapillus and Babylonia japonica. Aquatic Toxicology 199: 103-115.
Weninger W., Rendl M., Mildner M. and Tschachler E. (1998) Retinoids downregulate vascular endothelial growth factor/vascular permeability factor production by normal human keratinocytes. Journal of investigative dermatology 111(5): 907-911.
Yadav P., Bandyopadhyay A., Chakraborty A. and Sarkar K. (2018) Enhancement of anticancer activity and drug delivery of chitosan-curcumin nanoparticle via molecular docking and simulation analysis. Carbohydrate polymers 182: 188-198.
Zhang J. (2015) The Hybrid Idea of Optimization Methods Applied to the Energy Minimization of (Prion) Protein Structures Focusing on the beta2-alpha2 Loop. arXiv preprint arXiv:1504.03614.
Zhong G., Ortiz D., Zelter A., Nath A. and Isoherranen N. (2018) CYP26C1 is a hydroxylase of multiple active retinoids and interacts with cellular retinoic acid binding proteins. Molecular pharmacology 93(5): 489-503.
Zhu H., Hu J., Li X., Chen L., Zhao H., Zhou W. and et al. (2015). All‐trans retinoic acid and arsenic combination therapy benefits low‐to‐intermediate‐risk patients with newly diagnosed acute promyelocytic leukaemia: a long‐term follow‐up based on multivariate analysis. British journal of haematology 171(2): 277-280.