Department of Neurosurgery, 2Nd Affiliated Hospital, School of Medicine, Zhejiang University, 88# Jiefang Road, Hangzhou, 310009, Zhejiang, China.
Department of Pathology, 2Nd Affiliated Hospital, School of Medicine, Zhejiang University, 88# Jiefang Road, Hangzhou, 310009, Zhejiang, China.
Cell Commun Signal. 2021 Mar 24;19(1):40. doi: 10.1186/s12964-021-00729-8.
Lysosome-associated membrane protein type 2A (LAMP-2A) is the key component of chaperone-mediated autophagy (CMA), a cargo-selective lysosomal degradation pathway. Aberrant LAMP-2A expression and CMA activation have been demonstrated in various human malignancies. The study focusing on the intrinsic role of LAMP-2A and CMA in glioblastoma (GBM), and downstream mechanism could provide valuable insight into the pathogenesis and novel therapeutic modality of GBM.
The levels of LAMP-2A, nuclear receptor co-repressor (N-CoR), unfolded protein response (UPR) and apoptosis were examined in clinical samples. LAMP-2A siRNA and shRNA were constructed to manipulate CMA activation. The role of CMA and downstream mechanism through degradation of N-CoR and arresting UPR mediated apoptosis were explored in GBM cells and nude mouse xenograft model.
Elevated LAMP-2A and associated decreased N-CoR expression were observed in GBM as compared with peritumoral region and low-grade glioma. Inhibited UPR and apoptosis were observed in GBM with high LAMP-2A expression. In vitro study demonstrated co-localization and interaction between LAMP-2A and N-CoR. LAMP-2A silencing up-regulated N-CoR and aroused UPR pathway, leading to apoptosis, while N-CoR silencing led to an opposite result. In vivo study further confirmed that LAMP-2A inhibition arrested tumor growth by promoting apoptosis.
Our results demonstrated the central role of CMA in mediating N-CoR degradation and protecting GBM cells against UPR and apoptosis, and provided evidence of LAMP-2A as potential biomarker. Further research focusing on CMA with other tumorigenic process is needed and selective modulators of LAMP-2A remain to be investigated to provide a novel therapeutic strategy for GBM. Video Abstract.
溶酶体相关膜蛋白 2A（LAMP-2A）是伴侣介导的自噬（CMA）的关键组成部分，CMA 是一种货物选择性溶酶体降解途径。在各种人类恶性肿瘤中已经证明了异常的 LAMP-2A 表达和 CMA 激活。这项研究集中在 LAMP-2A 和 CMA 在胶质母细胞瘤（GBM）中的内在作用及其下游机制，可能为 GBM 的发病机制和新的治疗方式提供有价值的见解。
在临床样本中检查了 LAMP-2A、核受体共抑制因子（N-CoR）、未折叠蛋白反应（UPR）和细胞凋亡的水平。构建了 LAMP-2A siRNA 和 shRNA 来操纵 CMA 激活。在 GBM 细胞和裸鼠异种移植模型中，通过降解 N-CoR 和阻止 UPR 介导的细胞凋亡来探索 CMA 及其下游机制的作用。
与肿瘤周围区域和低级别神经胶质瘤相比，GBM 中观察到 LAMP-2A 升高和相关的 N-CoR 表达降低。在 LAMP-2A 高表达的 GBM 中观察到 UPR 抑制和细胞凋亡。体外研究表明 LAMP-2A 与 N-CoR 之间存在共定位和相互作用。LAMP-2A 沉默上调了 N-CoR 并激活了 UPR 途径，导致细胞凋亡，而 N-CoR 沉默则导致相反的结果。体内研究进一步证实，LAMP-2A 抑制通过促进细胞凋亡来阻止肿瘤生长。
我们的结果表明，CMA 在介导 N-CoR 降解并保护 GBM 细胞免受 UPR 和细胞凋亡方面发挥着核心作用，并为 LAMP-2A 作为潜在的生物标志物提供了证据。需要进一步研究 CMA 与其他肿瘤发生过程的关系，并研究 LAMP-2A 的选择性调节剂，为 GBM 提供新的治疗策略。视频摘要。
