Chaperone-Mediated Autophagy-Dependent Chemoresistance in Non-Small Cell Lung Cancer

Introduction: Chaperone-mediated autophagy (CMA) is a selective type of autophagy whereby a specific subset of intracellular proteins is targeted to the lysosome for degradation. Although macroautophagy is known to serve as a survival pathway in non-small cell lung cancer (NSCLC), the roles of CMA in NSCLC are not fully understood. Methods: Using human NSCLC tissues and normal tissues, immunohistochemical staining was performed to evaluate the expression level of lysosome-associated membrane protein type 2a (LAMP2A) that is known to function biologically in lysosomes as the translocator for CMA. ShRNA-mediated knockdown experiments of LAMP2A in NSCLC cell lines were conducted to elucidate the roles of LAMP2A in cancer malignancy including chemoresistance. To clarify the clinical relevance of LAMP2A in chemoresistant NSCLC patients, the LAMP2A expression levels in platinum-sensitive and -resistant NSCLC patients were evaluated. Results: We found that LAMP2A is highly expressed in NSCLC tissues compared to normal tissues. The high expression of LAMP2A in NSCLC is significantly related to poor prognosis. Further investigations showed that LAMP2A regulated tumor growth, and cytotoxic drug-resistance in both in vitro and in vivo. Finally, we found that the expression of LAMP2A in platinum-resistance NSCLC (n=17) is higher than that in platinum-sensitive NSCLC patients (n=19). Conclusion: These data suggest that LAMP2A is at least partly responsible for cancer chemoresistant phenotype and represents a promising new therapeutic target against NSCLC through CMA regulation.