PDF(Pubmed)
Abstract：
Tumor stemness is associated with the recurrence and incurability of colorectal cancer (CRC), which lacks effective therapeutic targets and drugs. Glycinamide ribonucleotide transformylase (GART) fulfills an important role in numerous types of malignancies. The present study aims to identify the underlying mechanism through which GART may promote CRC stemness, as to developing novel therapeutic methods. An elevated level of GART is associated with poor outcomes in CRC patients and promotes the proliferation and migration of CRC cells. CD133+ cells with increased GART expression possess higher tumorigenic and proliferative capabilities both in vitro and in vivo. GART is identified to have a novel methyltransferase function, whose enzymatic activity center is located at the E948 site. GART also enhances the stability of RuvB-like AAA ATPase 1 (RUVBL1) through methylating its K7 site, which consequently aberrantly activates the Wnt/β-catenin signaling pathway to induce tumor stemness. Pemetrexed (PEM), a compound targeting GART, combined with other chemotherapy drugs greatly suppresses tumor growth both in a PDX model and in CRC patients. The present study demonstrates a novel methyltransferase function of GART and the role of the GART/RUVBL1/β-catenin signaling axis in promoting CRC stemness. PEM may be a promising therapeutic agent for the treatment of CRC.
摘要：
肿瘤干性与结直肠癌（CRC）的复发和侵袭性有关，缺乏有效的治疗靶点和药物。甘氨酰胺核糖核苷酸转化酶（GART）在许多类型的恶性肿瘤中发挥重要作用。本研究旨在确定GART促进CRC干性的潜在机制。开发新的治疗方法。GART水平升高与CRC患者的不良预后相关，并促进CRC细胞的增殖和迁移。具有增加的GART表达的CD133+细胞在体外和体内都具有较高的致瘤和增殖能力。GART被鉴定为具有新的甲基转移酶功能，其酶活性中心位于E948位点。GART还通过甲基化其K7位点增强RuvB样AAAATP酶1（RUVBL1）的稳定性，从而异常激活Wnt/β-catenin信号通路以诱导肿瘤干性。培美曲塞(PEM),一种靶向GART的化合物，在PDX模型和CRC患者中,联合其他化疗药物极大地抑制了肿瘤生长.本研究证明了GART的新型甲基转移酶功能以及GART/RUVBL1/β-catenin信号轴在促进CRC干性中的作用。PEM可能是治疗CRC的有前途的治疗剂。
