基于靶点蛋白NR4A1三维结构的新型结直肠癌药物研究

Abstract: Orphan nuclear receptor NR4A1 is highly expressed as an oncogene in colorectal cancer. NR4A1 plays a transcriptional activation role in the nucleus, and promotes cell proliferation through interaction with Sp1 and p53. After the nuclear export of NR4A1, apoptosis is induced by the apoptosis complex, which is composed of NR4A1 and Bcl-2. Earlier work shows that the small molecule compound IMCA inhibits the proliferation and induces apoptosis via NR4A1 in colorectal cancer cells. Animal pretest showed that IMCA significantly inhibits the growth of subcutaneous transplanted tumor of colorectal cancer. Therefore, we put forward the hypothesis that IMCA plays the role of anti-colorectal cancer by regulating the proliferation and apoptosis via NR4A1. In Specific Aim 1 of this proposal, we will investigate the direct interaction between IMCA and NR4A1 at molecular level. In Specific Aim 2, the pharmacological mechanism of IMCA against colorectal cancer will be studied in vitro. In addition, the regulatory mechanism of IMCA against tumor growth and related toxicity of IMCA will also be examined in vivo. The antitumor activity of IMCA is the first discovery in our research group, and all of the content in this project is the first study. The results may provide new candidates for colorectal cancer therapy, and provide clues for other tumor therapies.

摘要：孤儿核受体NR4A1作为致癌基因在结直肠癌中高表达，其在细胞核内发挥转录激活作用，并通过与sp1、p53相互作用促进细胞增殖，但当其被诱导出细胞核后，能与Bcl-2形成凋亡复合体定位到线粒体引起细胞凋亡从而抑制癌细胞存活。前期工作表明，小分子化合物IMCA通过NR4A1显著抑制结直肠癌细胞的体外增殖，诱导细胞凋亡；动物预实验表明，IMCA显著抑制结直肠癌皮下移植瘤的生长。因此，我们提出“IMCA通过调节NR4A1介导的细胞增殖与凋亡途径，阻滞结直肠癌”的假说。本研究拟：⑴ 在分子水平上考察IMCA与NR4A1的直接相互作用；⑵ 体外研究IMCA抗结直肠癌的药理机制；⑶ 体内考察IMCA抗肿瘤生长的调控机制及相关毒性研究。IMCA抗肿瘤活性为本课题组首次发现，本项目内容均属首次研究，所得结果可能为结直肠癌治疗提供新的选择，并对其他肿瘤治疗提供新线索。

结直肠癌是常见的恶性肿瘤之一，据2020年全球185个国家36种肿瘤统计报告，结直肠癌在男、女性肿瘤发病率中均位居前三位，已经成为亟待解决的公共卫生问题。苯并吡喃又称为色烯，其衍生物已被研究多年，并发现了部分治疗应用，包括抗肿瘤活性。IMCA为苯并吡喃衍生物，本项目首次发现IMCA具有显著抗结直肠癌活性。本项目通过细胞实验和结直肠癌BALB/C裸鼠皮下荷瘤实验在体内外确定IMCA显著阻滞结直肠癌药效活性。本项目在分子、细胞和动物整体水平上评价IMCA阻滞结直肠癌的药效学活性，并深入研究其药理机制。研究结果揭示：（1）IMCA在体外显著抑制结直肠癌细胞活力；（2）IMCA在BALB/C荷瘤裸鼠体内显著抑制结直肠癌生长，并在荷瘤裸鼠体内均表现可忽略的毒副作用；（3）过表达并纯化NR4A1，等温滴定量热实验确定NR4A1与IMCA无直接相互作用；（4）转录组测序发现IMCA经铁死亡途径阻滞结直肠癌；（5）确定IMCA通过TFR/SLC7A11双靶点诱导结直肠癌细胞铁死亡。IMCA抗肿瘤活性为本课题组首次发现，本项目内容均属首次研究，所得结果可能为结直肠癌治疗和苯并吡喃化合物应用提供新的选择，并对其他肿瘤治疗提供新线索。

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