BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

MMPP is a novel VEGFR2 inhibitor that suppresses angiogenesis via VEGFR2/AKT/ERK/NF-κB pathway

  • Na-Yeon Kim (Department of Bioscience and Biotechnology, Konkuk University) ;
  • Hyo-Min Park (Department of Bioscience and Biotechnology, Konkuk University) ;
  • Jae-Young Park (Department of Bioscience and Biotechnology, Konkuk University) ;
  • Uijin Kim (Department of Biomedical Science and Engineering, Konkuk University) ;
  • Ha Youn Shin (Department of Biomedical Science and Engineering, Konkuk University) ;
  • Hee Pom Lee (College of Pharmacy & Medical Research Center, Chungbuk National University) ;
  • Jin Tae Hong (College of Pharmacy & Medical Research Center, Chungbuk National University) ;
  • Do-Young Yoon (Department of Bioscience and Biotechnology, Konkuk University)
  • Received : 2023.08.16
  • Accepted : 2023.11.03
  • Published : 2024.05.31
Download PDF
⟨ Previous Next ⟩

Abstract

Many types of cancer are associated with excessive angiogenesis. Anti-angiogenic treatment is an effective strategy for treating solid cancers. This study aimed to demonstrate the inhibitory effects of (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol (MMPP) in VEGFA-induced angiogenesis. The results indicated that MMPP effectively suppressed various angiogenic processes, such as cell migration, invasion, tube formation, and sprouting of new vessels in human umbilical vein endothelial cells (HUVECs) and mouse aortic ring. The inhibitory mechanism of MMPP on angiogenesis involves targeting VEGFR2. MMPP showed high binding affinity for the VEGFR2 ATP-binding domain. Additionally, MMPP improved VEGFR2 thermal stability and inhibited VEGFR2 kinase activity, suppressing the downstream VEGFR2/AKT/ERK pathway. MMPP attenuated the activation and nuclear translocation of NF-κB, and it downregulated NF-κB target genes such as VEGFA, VEGFR2, MMP2, and MMP9. Furthermore, conditioned medium from MMPP-treated breast cancer cells effectively inhibited angiogenesis in endothelial cells. These results suggested that MMPP had great promise as a novel VEGFR2 inhibitor with potent anti-angiogenic properties for cancer treatment via VEGFR2/AKT/ERK/NF-κB signaling pathway.

Keywords

References

  1. Siegel RL, Miller KD, Wagle NS and Jemal A (2023) Cancer statistics, 2023. CA Cancer J Clin 73, 17-48 https://doi.org/10.3322/caac.21763
  2. Neufeld G, Cohen T, Gengrinovitch S and Poltorak Z (1999) Vascular endothelial growth factor (VEGF) and its receptors. FASEB J 13, 9-22 https://doi.org/10.1096/fasebj.13.1.9
  3. Hanahan D and Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86, 353-364 https://doi.org/10.1016/S0092-8674(00)80108-7
  4. Li T, Kang G, Wang T and Huang H (2018) Tumor angiogenesis and anti-angiogenic gene therapy for cancer. Oncol Lett 16, 687-702 https://doi.org/10.3892/ol.2018.8733
  5. Kowanetz M and Ferrara N (2006) Vascular endothelial growth factor signaling pathways: therapeutic perspective. Clin Cancer Res 12, 5018-5022 https://doi.org/10.1158/1078-0432.CCR-06-1520
  6. Shah AA, Kamal MA and Akhtar S (2021) Tumor Angiogenesis and VEGFR-2: mechanism, pathways and current biological therapeutic interventions. Curr Drug Metab 22, 50-59
  7. Kim NY, Lim CM, Park HM et al (2022) MMPP promotes adipogenesis and glucose uptake via binding to the PPARgamma ligand binding domain in 3T3-L1 MBX cells. Front Pharmacol 13, 994584
  8. Son DJ, Zheng J, Jung YY et al (2017) MMPP attenuates non-small cell lung cancer growth by inhibiting the STAT3 DNA-binding activity via direct binding to the STAT3 DNA-binding domain. Theranostics 7, 4632-4642 https://doi.org/10.7150/thno.18630
  9. Kim SJ, Song YS, Pham TH et al (2018) (E)-2-Methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol attenuates PMA-induced inflammatory responses in human monocytic cells through PKCdelta/JNK/AP-1 pathways. Eur J Pharmacol 825, 19-27 https://doi.org/10.1016/j.ejphar.2018.01.024
  10. Bhanushali U, Rajendran S, Sarma K et al (2016) 5-Benzylidene-2,4-thiazolidenedione derivatives: design, synthesis and evaluation as inhibitors of angiogenesis targeting VEGR-2. Bioorg Chem 67, 139-147 https://doi.org/10.1016/j.bioorg.2016.06.006
  11. Peng FW, Liu DK, Zhang QW, Xu YG and Shi L (2017) VEGFR-2 inhibitors and the therapeutic applications thereof: a patent review (2012-2016). Expert Opin Ther Pat 27, 987-1004 https://doi.org/10.1080/13543776.2017.1344215
  12. Zhang M, Liu J, Liu G et al (2021) Anti-vascular endothelial growth factor therapy in breast cancer: molecular pathway, potential targets, and current treatment strategies. Cancer Lett 520, 422-433 https://doi.org/10.1016/j.canlet.2021.08.005
  13. Al-Sanea MM, Chilingaryan G, Abelyan N et al (2021) Identification of novel potential VEGFR-2 inhibitors using a combination of computational methods for drug discovery. Life (Basel) 11, 1070
  14. Liu Y, Li Y, Wang Y et al (2022) Recent progress on vascular endothelial growth factor receptor inhibitors with dual targeting capabilities for tumor therapy. J Hematol Oncol 15, 89
  15. Simons M, Gordon E and Claesson-Welsh L (2016) Mechanisms and regulation of endothelial VEGF receptor signalling. Nat Rev Mol Cell Biol 17, 611-625 https://doi.org/10.1038/nrm.2016.87
  16. Sakai R, Henderson JT, O'Bryan JP, Elia AJ, Saxton TM and Pawson T (2000) The mammalian ShcB and ShcC phosphotyrosine docking proteins function in the maturation of sensory and sympathetic neurons. Neuron 28, 819-833 https://doi.org/10.1016/S0896-6273(00)00156-2
  17. Dolcet X, Llobet D, Pallares J and Matias-Guiu X (2005) NF-kB in development and progression of human cancer. Virchows Arch 446, 475-482 https://doi.org/10.1007/s00428-005-1264-9
  18. Madrid LV, Mayo MW, Reuther JY and Baldwin AS, Jr. (2001) Akt stimulates the transactivation potential of the RelA/p65 Subunit of NF-kappa B through utilization of the Ikappa B kinase and activation of the mitogen-activated protein kinase p38. J Biol Chem 276, 18934-18940 https://doi.org/10.1074/jbc.M101103200
  19. Tu J, Fang Y, Han D et al (2021) Activation of nuclear factor-kappaB in the angiogenesis of glioma: insights into the associated molecular mechanisms and targeted therapies. Cell Prolif 54, e12929
  20. Dong F, Zhou X, Li C et al (2014) Dihydroartemisinin targets VEGFR2 via the NF-kappaB pathway in endothelial cells to inhibit angiogenesis. Cancer Biol Ther 15, 1479-1488 https://doi.org/10.4161/15384047.2014.955728
  21. Tabruyn SP and Griffioen AW (2008) NF-kappa B: a new player in angiostatic therapy. Angiogenesis 11, 101-106 https://doi.org/10.1007/s10456-008-9094-4
  22. Wiszniak S and Schwarz Q (2021) Exploring the Intracrine Functions of VEGF-A. Biomolecules 11, 108
  23. Zheng H, Takahashi H, Murai Y et al (2006) Expressions of MMP-2, MMP-9 and VEGF are closely linked to growth, invasion, metastasis and angiogenesis of gastric carcinoma. Anticancer Res 26, 3579-3583
  24. Son DJ, Kim DH, Nah SS et al (2016) Novel synthetic (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol inhibits arthritis by targeting signal transducer and activator of transcription 3. Sci Rep 6, 36852
  25. Trott O and Olson AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31, 455-461 https://doi.org/10.1002/jcc.21334
  26. Eldehna WM, Fares M, Ibrahim HS et al (2015) Indoline ureas as potential anti-hepatocellular carcinoma agents targeting VEGFR-2: synthesis, in vitro biological evaluation and molecular docking. Eur J Med Chem 100, 89-97 https://doi.org/10.1016/j.ejmech.2015.05.040
  27. Biovia DS (2016) Discovery Studio Modeling Environment. Dassault Systemes: San Diego, CA, USA
  28. Upadhyay N, Tilekar K, Safuan S et al (2021) Double-edged Swords: diaryl pyrazoline thiazolidinediones synchronously targeting cancer epigenetics and angiogenesis. Bioorg Chem 116, 105350
  29. Schneider CA, Rasband WS and Eliceiri KW (2012) NIH Image to ImageJ: 25 years of image analysis. Nat Methods 9, 671-675
  30. Arnaoutova I and Kleinman HK (2010) In vitro angiogenesis: endothelial cell tube formation on gelled basement membrane extract. Nat Protoc 5, 628-635 https://doi.org/10.1038/nprot.2010.6
  31. 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
  32. Baker M, Robinson SD, Lechertier T et al (2011) Use of the mouse aortic ring assay to study angiogenesis. Nat Protoc 7, 89-104
  33. Jafari R, Almqvist H, Axelsson H et al (2014) The cellular thermal shift assay for evaluating drug target interactions in cells. Nat Protoc 9, 2100-2122 https://doi.org/10.1038/nprot.2014.138