Brodowska Katarzyna, Al-Moujahed Ahmad, Marmalidou Anna, Meyer Zu Horste Melissa, Cichy Joanna, Miller Joan W, Gragoudas Evangelos, Vavvas Demetrios G
Harvard Medical School, Retina Service, Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Boston, MA 02114, USA.
Dept. of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
Exp Eye Res. 2014 Jul;124:67-73. doi: 10.1016/j.exer.2014.04.011. Epub 2014 May 15.
Verteporfin (VP), a benzoporphyrin derivative, is clinically used in photodynamic therapy for neovascular macular degeneration. Recent studies indicate that VP may inhibit growth of hepatoma cells without photoactivation through inhibition of YAP-TEAD complex. In this study, we examined the effects of VP without light activation on human retinoblastoma cell lines. Verteporfin but not vehicle control inhibited the growth, proliferation and viability of human retinoblastoma cell lines (Y79 and WERI) in a dose-dependent manner and was associated with downregulation of YAP-TEAD associated downstream proto-oncogenes such as c-myc, Axl, and surviving. In addition VP affected signals involved in cell migration and angiogenesis such as CTGF, cyr61, and VEGF-A but was not associated with significant effect on the mTOR/autophagy pathway. Of interest the pluripotency marker Oct4 were downregulated by Verteporfin treatment. Our results indicate that the clinically used photosensitizer VP is a potent inhibitor of cell growth in retinoblastoma cells, disrupting YAP-TEAD signaling and pluripotential marker OCT4. This study highlights for the first time the role of the YAP-TEAD pathway in Retinoblastoma and suggests that VP may be a useful adjuvant therapeutic tool in treating Rb patients.
维替泊芬(VP)是一种苯并卟啉衍生物,临床上用于治疗新生血管性黄斑变性的光动力疗法。最近的研究表明,VP可能通过抑制YAP-TEAD复合物,在无光激活的情况下抑制肝癌细胞的生长。在本研究中,我们检测了无光激活的VP对人视网膜母细胞瘤细胞系的影响。维替泊芬而非溶剂对照以剂量依赖性方式抑制人视网膜母细胞瘤细胞系(Y79和WERI)的生长、增殖和活力,并与YAP-TEAD相关的下游原癌基因如c-myc、Axl和Survivin的下调有关。此外,VP影响参与细胞迁移和血管生成的信号,如结缔组织生长因子(CTGF)、富含半胱氨酸的血管生成素61(Cyr61)和血管内皮生长因子A(VEGF-A),但对mTOR/自噬途径无显著影响。有趣的是,维替泊芬处理下调了多能性标志物Oct4。我们的结果表明,临床使用的光敏剂VP是视网膜母细胞瘤细胞生长的有效抑制剂,可破坏YAP-TEAD信号传导和多能性标志物OCT4。本研究首次强调了YAP-TEAD途径在视网膜母细胞瘤中的作用,并表明VP可能是治疗视网膜母细胞瘤患者的有用辅助治疗工具。