Khageh Hosseini Sabrina, Kolterer Stefanie, Steiner Marlene, von Manstein Viktoria, Gerlach Katharina, Trojan Jörg, Waidmann Oliver, Zeuzem Stefan, Schulze Jörg O, Hahn Steffen, Steinhilber Dieter, Gatterdam Volker, Tampé Robert, Biondi Ricardo M, Proschak Ewgenij, Zörnig Martin
Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Paul-Ehrlich-Strasse 42-44, D-60596 Frankfurt/Main, Germany.
Department of Internal Medicine I, University Hospital Frankfurt, Theodor-Stern-Kai 7, D-60590 Frankfurt/Main, Germany; Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society, Buenos Aires C1425FQD, Argentina.
Biochem Pharmacol. 2017 Dec 15;146:53-62. doi: 10.1016/j.bcp.2017.10.003. Epub 2017 Oct 13.
The transcriptional regulator FUSE Binding Protein 1 (FUBP1) is overexpressed in more than 80% of all human hepatocellular carcinomas (HCCs) and other solid tumor entities including prostate and colorectal carcinoma. FUBP1 expression is required for HCC tumor cell expansion, and it functions as an important pro-proliferative and anti-apoptotic oncoprotein that binds to the single-stranded DNA sequence FUSE to regulate the transcription of a variety of target genes. In this study, we screened an FDA-approved drug library and discovered that the Topoisomerase I (TOP1) inhibitor camptothecin (CPT) and its derivative 7-ethyl-10-hydroxycamptothecin (SN-38), the active irinotecan metabolite that is used in the clinics in combination with other chemotherapeutics to treat carcinoma, inhibit FUBP1 activity. Both molecules prevent in vitro the binding of FUBP1 to its single-stranded target DNA FUSE, and they induce deregulation of FUBP1 target genes in HCC cells. Our results suggest the interference with the FUBP1/FUSE interaction as a further molecular mechanism that, in addition to the inactivation of TOP1, may contribute to the therapeutic potential of CPT/SN-38. Targeting of FUBP1 in HCC therapy with SN-38/irinotecan could be a particularly interesting option because of the high FUBP1 levels in HCC cells and their dependency on FUBP1 expression.
转录调节因子融合结合蛋白1（FUBP1）在超过80%的人类肝细胞癌（HCC）以及包括前列腺癌和结直肠癌在内的其他实体瘤中过表达。FUBP1的表达是HCC肿瘤细胞扩增所必需的，它作为一种重要的促增殖和抗凋亡癌蛋白，与单链DNA序列FUSE结合，以调节多种靶基因的转录。在本研究中，我们筛选了一个FDA批准的药物库，发现拓扑异构酶I（TOP1）抑制剂喜树碱（CPT）及其衍生物7-乙基-10-羟基喜树碱（SN-38），即临床上与其他化疗药物联合用于治疗癌症的活性伊立替康代谢物，可抑制FUBP1活性。这两种分子在体外均可阻止FUBP1与其单链靶DNA FUSE的结合，并诱导HCC细胞中FUBP1靶基因的失调。我们的结果表明，除了TOP1失活外，干扰FUBP1/FUSE相互作用是另一种分子机制，可能有助于CPT/SN-38的治疗潜力。由于HCC细胞中FUBP1水平较高且它们依赖于FUBP1表达，因此在HCC治疗中用SN-38/伊立替康靶向FUBP1可能是一个特别有吸引力的选择。
