NEDD4L通过调控多发性骨髓瘤自噬信号通路介导硼替佐米耐药的分子机制

Multiple Myeloma (MM) is a malignant tumor with abnormal proliferation of monoclonal plasma cell, proteasome inhibitor bortezomib is one of the most effective drugs in treatment of MM, but still with primary and secondary resistance. Autophagy in MM cells that synthesize and secrete mass immunoglobulins is significantly activated by a large amount of unfolded or misfolded protein in the endoplasmic reticulum. Our previous studies showed that inhibition of autophagy resulted in an antagonistic response to Bor. The ubiquitin–proteasome system has been demonstrated to regulate the level of autophagy. NEDD4L is one of the variety of ubiquitin E3 ligases. We found that knockdown of NEDD4L in MM cells induced Bor-resistance. Consistently, UPR effector glucose-regulated protein 78 (GRP78) and autophagy associated protein LC3, Atg5 were downregulated. Taken together, our foundings provided a evidence that NEDD4L induces an autophagic response which can enhance the sensitivity of MM cells to bortezomib. The project is focused on the function of ubiquitylation between NEDD4L and substrates in MM autophagy, to further explore how to enhance the Bor-induced apoptosis by modulating NEDD4L effectively for providing theoretical basis for new targets of MM.

多发性骨髓瘤（MM）是一种单克隆浆细胞异常增生的恶性肿瘤，蛋白酶体抑制剂硼替佐米（Bor）是目前治疗MM最有效的药物之一，但仍存在原发及继发耐药。MM细胞具有极高的免疫球蛋白合成与分泌活性，其内质网中存在大量未折叠或错误折叠蛋白，从而引起较强的自噬反应。研究已证实泛素化蛋白酶体途径与自噬溶酶体途径存在交互作用。NEDD4L是参与其中的一个关键E3连接酶，我们发现下调NEDD4L可以抑制Bor的杀伤效果，同时UPR效应分子GRP78和自噬相关蛋白LC3、Atg5等表达明显下调。前期研究还表明自噬抑制剂可以拮抗Bor的疗效。因此我们推测NEDD4L可以正向调控MM细胞中的自噬信号通路，从而介导Bor的耐药。本项目拟深入研究NEDD4L与底物的泛素化作用在调控MM细胞自噬过程中的功能，进而寻求如何通过有效调节NEDD4L来增强Bor的治疗效果，为研究MM治疗的新靶点和新药物分子设计提供理论依据。

多发性骨髓瘤(MM)仍然是一种无法治愈的浆细胞癌，以异常分泌单克隆免疫球蛋白为特征。MM细胞药物敏感性调控的分子机制正在被深入研究。在这里，我们报道了一个意想不到的发现，神经前体细胞表达发育下调基因4L (NEDD4L)，一种HECT E3连接酶，结合19S蛋白酶体，限制其蛋白水解功能并增强自噬。NEDD4L表达的抑制降低了硼替佐米(Bor)在体内和体外的敏感性，主要是通过低NEDD4L表达介导的自噬抑制，自噬激活剂挽救了这一抑制。临床上，NEDD4L表达的升高与对Bor反应的概率显著增加、反应持续时间延长和总体预后改善有关，支持NEDD4L作为生物标记物的使用，以确定最可能从Bor获益的患者，以及NEDD4L作为骨髓瘤治疗的新方法的调节。