Abstract
Aggresomes are transient microtubule-dependent inclusion bodies that sequester misfolded proteins and are ultimately removed by autophagy. Here we report the generation of a choroid plexus carcinoma cell line; Children’s Cancer Hospital Egypt (CCHE)-45, which is characterized by the constitutive formation of aggresomes. When examining the autophagy pathway as the main route for aggresomes clearance, CCHE-45 cells displayed increased autophagy flux mediated by MAP1LC3B. MAP1LC3A-Variant1 gene expression was silenced by promoter methylation. Restoring MAP1LC3A-Variant1 expression resulted in the formation of MAP1LC3A positive autophagosmes and the disruption of the aggresomes' vimentin cage independent of MAP1LC3B positive autophagosomes. Our data supports the notion that basal quality control autophagy and vimentin cage clearance in CCHE-45 are mediated by MAP1LC3A. Hence we propose that absence of MAP1LC3A disrupts the autophagic pathway and leads to the failure of aggresome vimentin cage degradation. Consequently, this could represent a targetable pathway in autophagy-dependent cancers.
Highlights
Autophagy was initially characterized as a non-selective cellular degradation mechanism that is initiated by nutrient deprivation[7]
We investigate the role of autophagy in aggresome clearance in choroid plexus carcinoma tumors (CPCTs)
Juxta Nuclear Quality control compartment (JUNQ) describes vimentin-positive structures that share similar cellular positions as aggresomes[16], and it was proposed that aggresomes may represent a mature state of JUNQ3
Summary
Autophagy was initially characterized as a non-selective cellular degradation mechanism that is initiated by nutrient deprivation[7]. We investigate the role of autophagy in aggresome clearance in choroid plexus carcinoma tumors (CPCTs). CPCTs are rare neoplasms of the central nervous system, with 20% of tumors occurring during the first year of life[12, 13]. These patients generally have poor outcomes due to limited therapeutic options[5, 14]. Results suggest that LC3A gene silencing in CPC primes cells for aggresome formation to achieve cellular homeostasis, highlighting the role of aggresomes as a survival mechanism for cancer cells
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