10月10日，厦门大学药学院“千人计划”专家张晓坤教授的课题组在国际著名肿瘤学刊物《癌基因》（Oncogene）上发表了重要研究论文。该项研究是与我国著名的天然产物研究专家姚新生院士的课题组强强合作而进行的，对结肠癌的机制和治疗方法做了新的探索，发现了抑制肿瘤细胞生长的潜在治疗靶点和药物。
β-catenin是一种多功能蛋白质，其主要功能是介导细胞间黏附和参与基因的表达调控，其表达量受到APC等相关蛋白的严密调控；近期的研究表明，由于APC及其相关基因的突变，导致β-catenin异常积累与结肠癌的发生密切相关。因此，寻找一种新的不依赖于APC的β-catenin表达调控途径对于结肠癌的治疗具有极其重要的意义。该研究发现孤儿核受体Nur77可以通过其非基因型功能负调控β-catenin的表达，从而起到抑制肿瘤细胞生长的作用。同时，该研究还发现了两个可以通过诱导Nur77的表达而对β-catenin的表达起到负调控作用的强心苷类小分子化合物：H-9和ATE-i2-b4。该研究从分子、细胞和动物水平上证明Nur77可以作为结肠癌治疗的潜在靶点，H-9和ATE-i2-b4则可能成为治疗结肠癌的潜在药物。
该论文的第一作者为厦门大学药学院博士生孙哲；通讯作者为张晓坤教授和姚新生院士。近年来，张晓坤教授及其课题组在癌症研究领域已取得许多重大成果，先后在国际高水平杂志上以厦门大学为第一或通讯作者单位发表了多篇论文，杂志包括Cancer Cell（JCR一区，影响因子26.925）、Cancer Res（JCR一区，影响因子8.234）、FASEB J（JCR二区，影响因子6.515）、Oncogene（JCR一区，影响因子7.414）等。这些创新性的发现对于人类攻克癌症具有非常重要的理论和现实意义。(生物谷 Bioon.com)
doi:10.1038/onc.2011.448
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Inhibition of β-catenin signaling by nongenomic action of orphan nuclear receptor Nur77
Z Sun, X Cao, M-M Jiang, Y Qiu, H Zhou, L Chen, B Qin, H Wu, F Jiang, J Chen, J Liu, Y Dai, H-F Chen, Q-Y Hu, Z Wu, J-Z Zeng, X-S Yao and X-K Zhang
Dysregulation of β-catenin turnover due to mutations of its regulatory proteins including adenomatous polyposis coli (APC) and p53 is implicated in the pathogenesis of cancer. Thus, intensive effort is being made to search for alternative approaches to reduce abnormally activated β-catenin in cancer cells. Nur77, an orphan member of the nuclear receptor superfamily, has a role in the growth and apoptosis of cancer cells. Here, we reported that Nur77 could inhibit transcriptional activity of β-catenin by inducing β-catenin degradation via proteasomal degradation pathway that is glycogen synthase kinase 3β and Siah-1 independent. Nur77 induction of β-catenin degradation required both the N-terminal region of Nur77, which was involved in Nur77 ubiquitination, and the C-terminal region, which was responsible for β-catenin binding. Nur77/ΔDBD, a Nur77 mutant lacking its DNA-binding domain, resided in the cytoplasm, interacted with β-catenin, and induced β-catenin degradation, demonstrating that Nur77-mediated β-catenin degradation was independent of its DNA binding and transactivation, and might occur in the cytoplasm. In addition, we reported our identification of two digitalis-like compounds (DLCs), H-9 and ATE-i2-b4, which potently induced Nur77 expression and β-catenin degradation in SW620 colon cancer cells expressing mutant APC protein in vitro and in animals. DLC-induced Nur77 protein was mainly found in the cytoplasm, and inhibition of Nur77 nuclear export by the CRM1-dependent nuclear export inhibitor leptomycin B or Jun N-terminal kinase inhibitor prevented the effect of DLC on inducing β-catenin degradation. Together, our results demonstrate that β-catenin can be degraded by cytoplasmic Nur77 through their interaction and identify H-9 and ATE-i2-b4 as potent activators of the Nur77-mediated pathway for β-catenin degradation.
