Yongjie Wang1, Buyi Zhang2, Jianli Wang1, Haijian Wu1, Shenbin Xu1, Jianmin Zhang3, Lin Wang4. 1. Department of Neurosurgery, 2Nd Affiliated Hospital, School of Medicine, Zhejiang University, 88# Jiefang Road, Hangzhou, 310009, Zhejiang, China. 2. Department of Pathology, 2Nd Affiliated Hospital, School of Medicine, Zhejiang University, 88# Jiefang Road, Hangzhou, 310009, Zhejiang, China. 3. Department of Neurosurgery, 2Nd Affiliated Hospital, School of Medicine, Zhejiang University, 88# Jiefang Road, Hangzhou, 310009, Zhejiang, China. zjm135@zju.edu.cn. 4. Department of Neurosurgery, 2Nd Affiliated Hospital, School of Medicine, Zhejiang University, 88# Jiefang Road, Hangzhou, 310009, Zhejiang, China. dr_wang@zju.edu.cn.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Authors: Helin Vakifahmetoglu-Norberg; Minsu Kim; Hong-Guang Xia; Marcin P Iwanicki; Dimitry Ofengeim; Jonathan L Coloff; Lifeng Pan; Tan A Ince; Guido Kroemer; Joan S Brugge; Junying Yuan Journal: Genes Dev Date: 2013-08-01 Impact factor: 11.361
Authors: Rut Valdor; David García-Bernal; Dolores Riquelme; Carlos M Martinez; Jose M Moraleda; Ana Maria Cuervo; Fernando Macian; Salvador Martinez Journal: Proc Natl Acad Sci U S A Date: 2019-09-23 Impact factor: 11.205
Authors: Zehra Yildirim; Sabyasachi Baboo; Syed M Hamid; Asli E Dogan; Ozlem Tufanli; Sabrina Robichaud; Christina Emerton; Jolene K Diedrich; Hasan Vatandaslar; Fotis Nikolos; Yanghong Gu; Takao Iwawaki; Elizabeth Tarling; Mireille Ouimet; David L Nelson; John R Yates; Peter Walter; Ebru Erbay Journal: EMBO Mol Med Date: 2022-02-22 Impact factor: 12.137