Discovery of LAMP-2A as Potential Biomarkers for Glioblastoma Development by Modulating Apoptosis through N-CoR Degradation

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 reaction (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.

The Multifaceted Role of CMA in Glioma: Enemy or Ally?

“…Recent evidence shows that several tumors, including glioma, express high LAMP-2A levels, and this condition has been associated with a worse prognosis [ 69 ]. In GBM cells, a combined positivity to lysosomal LAMP-2A and intraluminal Cathepsin D has been described, even if the expression level of CMA-related genes was different among the analyzed cell lines (U87 vs. T98 glioma cells).…”