Abstract
BackgroundNeuroblastoma (NB) is the most frequently occurring solid tumor in children, and shows heterogeneous clinical behavior. Favorable tumors, which are usually detected by mass screening based on increased levels of catecholamines in urine, regress spontaneously via programmed cell death (PCD) or mature through differentiation into benign ganglioneuroma (GN). In contrast, advanced-type NB tumors often grow aggressively, despite intensive chemotherapy. Understanding the molecular mechanisms of PCD during spontaneous regression in favorable NB tumors, as well as identifying genes with a pro-death role, is a matter of urgency for developing novel approaches to the treatment of advanced-type NB tumors.Principal FindingsWe found that the expression of lysosomal associated protein multispanning transmembrane 5 (LAPTM5) was usually down-regulated due to DNA methylation in an NB cell-specific manner, but up-regulated in degenerating NB cells within locally regressing areas of favorable tumors detected by mass-screening. Experiments in vitro showed that not only a restoration of its expression but also the accumulation of LAPTM5 protein, was required to induce non-apoptotic cell death with autophagic vacuoles and lysosomal destabilization with lysosomal-membrane permeabilization (LMP) in a caspase-independent manner. While autophagy is a membrane-trafficking pathway to degrade the proteins in lysosomes, the LAPTM5-mediated lysosomal destabilization with LMP leads to an interruption of autophagic flux, resulting in the accumulation of immature autophagic vacuoles, p62/SQSTM1, and ubiqitinated proteins as substrates of autophagic degradation. In addition, ubiquitin-positive inclusion bodies appeared in degenerating NB cells.ConclusionsWe propose a novel molecular mechanism for PCD with the accumulation of autophagic vacuoles due to LAPTM5-mediated lysosomal destabilization. LAPTM5-induced cell death is lysosomal cell death with impaired autophagy, not cell death by autophagy, so-called autophagic cell death. Thus LAPTM5-mediated PCD is closely associated with the spontaneous regression of NBs and opens new avenues for exploring innovative clinical interventions for this tumor.
Highlights
Neuroblastoma (NB) is a malignant tumor consisting of undifferentiated neuroectodermal cells from the neural crest and the most common solid tumor in children
lysosomal associated protein multispanning transmembrane 5 (LAPTM5)-mediated programmed cell death (PCD) is closely associated with the spontaneous regression of NBs and opens new avenues for exploring innovative clinical interventions for this tumor
Screening for two candidate genes (MATN1 and LAPTM5) on this bacterial artificial chromosome (BAC) revealed that the expression of LAPTM5 was downregulated in NB cell lines and the CG sites around the transcriptional start site (TSS) of this gene were highly and widely methylated in both NB cell lines and primary NB tumors (Supplementary Figure S1, Supplementary Table S1, and Supplementary Methods S1), prompting us to focus on LAPTM5 as a candidate for an NB-related gene down-regulated through DNA methylation
Summary
Neuroblastoma (NB) is a malignant tumor consisting of undifferentiated neuroectodermal cells from the neural crest and the most common solid tumor in children. The clinical behavior of NB is heterogeneous: favorable tumors, which are usually detected by mass screening based on increased levels of catecholamines in urine, regress spontaneously via programmed cell death (PCD) or mature through differentiation into benign ganglioneuromas (GN) in patients under 1 year of age, with minimal or no therapeutic intervention; while advanced-type NBs, usually clinically detected, often grow rapidly to become fatal in older children, despite intensive chemotherapy [1,2,3]. Favorable tumors, which are usually detected by mass screening based on increased levels of catecholamines in urine, regress spontaneously via programmed cell death (PCD) or mature through differentiation into benign ganglioneuroma (GN). Understanding the molecular mechanisms of PCD during spontaneous regression in favorable NB tumors, as well as identifying genes with a pro-death role, is a matter of urgency for developing novel approaches to the treatment of advanced-type NB tumors
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