拮抗 SET 通过重新激活 PP2A 介导的 Akt 下调增强肝癌放射治疗的效果。
Antagonizing SET Augments the Effects of Radiation Therapy in Hepatocellular Carcinoma through Reactivation of PP2A-Mediated Akt Downregulation.
机构信息
Division of Radiation Oncology, Department of Oncology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan (C.-Y.H.); Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan (M.-H.H.); Institute of Biopharmaceutical Sciences (C.-T.S.) and School of Medicine (M.-H.H.), National Yang-Ming University, Taipei, Taiwan; Department of Medical Research (F.-S.H., M.-H.T., S.-S.C., Y.-J.H, L.-J.C., K.-F.C.) and National Center of Excellence for Clinical Trial and Research (K.-F.C.), National Taiwan University Hospital, Taipei, Taiwan; Department of Medical Imaging and Radiological Technology, Yuanpei University, Hsinchu, Taiwan (C.-Y.H., C.-W.K.); and SupremeCure Pharma Inc., Taipei, Taiwan (T.-I.C.).
Division of Radiation Oncology, Department of Oncology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan (C.-Y.H.); Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan (M.-H.H.); Institute of Biopharmaceutical Sciences (C.-T.S.) and School of Medicine (M.-H.H.), National Yang-Ming University, Taipei, Taiwan; Department of Medical Research (F.-S.H., M.-H.T., S.-S.C., Y.-J.H, L.-J.C., K.-F.C.) and National Center of Excellence for Clinical Trial and Research (K.-F.C.), National Taiwan University Hospital, Taipei, Taiwan; Department of Medical Imaging and Radiological Technology, Yuanpei University, Hsinchu, Taiwan (C.-Y.H., C.-W.K.); and SupremeCure Pharma Inc., Taipei, Taiwan (T.-I.C.)
出版信息
J Pharmacol Exp Ther. 2018 Sep;366(3):410-421. doi: 10.1124/jpet.118.249102. Epub 2018 Jun 18.
Increasing evidence suggests that SET functions as an oncoprotein and promotes cancer survival and therapeutic resistance. However, whether SET affects radiation therapy (RT)-mediated anticancer effects has not yet been explored. We investigated the impact of SET on RT sensitivity in hepatocellular carcinoma (HCC). Using colony and hepatosphere formation assays, we found that RT-induced proliferative inhibition was critically associated with SET expression. We next tested a novel SET antagonist, N-(3-ethynylphenyl)-6,7-dimethoxy-N-(4-phenoxyphenyl) quinazoline-2,4-diamine (EMQA), in combination with RT. We showed that additive use of EMQA significantly enhanced the effects of RT against HCC in vitro and in vivo. Notably, compared with mice receiving either RT or EMQA alone, the growth of PLC5 xenografted tumor in mice receiving RT plus EMQA was significantly reduced without compromising treatment tolerability. Furthermore, we proved that antagonizing SET to restore protein phosphatase 2A-mediated phospho-Akt (p-AKT) downregulation was responsible for the synergism between EMQA and RT. Our data demonstrate a new oncogenic property of SET and provide preclinical evidence that combining a SET antagonist and RT may be effective for treatment of HCC. Further investigation is warranted to validate the clinical relevance of this approach.
越来越多的证据表明，SET 作为一种癌蛋白发挥作用，促进癌症的存活和治疗耐药性。然而，SET 是否影响放射治疗（RT）介导的抗癌作用尚未被探索。我们研究了 SET 对肝癌（HCC）的 RT 敏感性的影响。通过集落和肝癌球体形成实验，我们发现 RT 诱导的增殖抑制与 SET 表达密切相关。接下来，我们测试了一种新型 SET 拮抗剂 N-(3-乙炔基苯基)-6,7-二甲氧基-N-(4-苯氧基苯基)喹唑啉-2,4-二胺（EMQA）与 RT 的联合应用。结果表明，EMQA 与 RT 的联合应用显著增强了 RT 对 HCC 的体外和体内抑制效果。值得注意的是，与单独接受 RT 或 EMQA 的小鼠相比，接受 RT 加 EMQA 治疗的小鼠的 PLC5 异种移植瘤的生长明显受到抑制，同时不影响治疗耐受性。此外，我们证明了拮抗 SET 以恢复蛋白磷酸酶 2A 介导的磷酸化 Akt（p-Akt）下调是 EMQA 和 RT 之间协同作用的原因。我们的数据揭示了 SET 的一种新的致癌特性，并提供了临床前证据，表明联合使用 SET 拮抗剂和 RT 可能对 HCC 的治疗有效。需要进一步的研究来验证这种方法的临床相关性。
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