Role of Chaperone Mediated Autophagy (CMA) in the Degradation of Misfolded N-CoR Protein in Non-Small Cell Lung Cancer (NSCLC) Cells

Abstract

Nuclear receptor co-repressor (N-CoR) plays important role in transcriptional control mediated by several tumor suppressor proteins. Recently, we reported a role of misfolded-conformation dependent loss (MCDL) of N-CoR in the activation of oncogenic survival pathway in acute promyelocytic leukemia (APL). Since N-CoR plays important role in cellular homeostasis in various tissues, therefore, we hypothesized that an APL like MCDL of N-CoR might also be involved in other malignancy. Indeed, our initial screening of N-CoR status in various leukemia and solid tumor cells revealed an APL like MCDL of N-CoR in primary and secondary tumor cells derived from non-small cell lung cancer (NSCLC). The NSCLC cell specific N-CoR loss could be blocked by Kaletra, a clinical grade protease inhibitor and by genistein, an inhibitor of N-CoR misfolding previously characterized by us. The misfolded N-CoR presented in NSCLC cells was linked to the amplification of ER stress and was subjected to degradation by NSCLC cell specific aberrant protease activity. In NSCLC cells, misfolded N-CoR was found to be associated with Hsc70, a molecular chaperone involved in chaperone mediated autophagy (CMA). Genetic and chemical inhibition of Lamp2A, a rate limiting factor of CMA, significantly blocked the loss of N-CoR in NSCLC cells, suggesting a crucial role of CMA in N-CoR degradation. These findings identify an important role of CMA-induced degradation of misfolded N-CoR in the neutralization of ER stress and suggest a possible role of misfolded N-CoR protein in the activation of oncogenic survival pathway in NSCLC cells.

Allicin activates autophagic cell death to alleviate the malignant development of thyroid cancer

“…Certain studies suggest that the pro-survival functions of autophagy decrease the efficacy of cancer therapeutics (20,25). However, other studies have demonstrated that autophagy also induced cancer cell death after various treatments (9,(28)(29)(30). Thus, activation of autophagic cell death is becoming an important strategy for cancer treatment.…”

Chaperone-mediated autophagy: roles in disease and aging

“…On the contrary, later experiments revealed that the multimerization of LAMP-2A is transient and that as soon as the substrate is translocated into the lumen, LAMP-2A disassembles from this complex in an hsc70-dependent manner [20]. The multimeric complex that mediates substrate translocation is of a defined size (700 kDa) and is composed mainly of LAMP-2A molecules but at least two other proteins can also be found associated to the complex [22,23] ( Kon et al, unpublished). Interestingly, these additional components seem important to regulate the stability of the multimeric complex but not essential for translocation, as inserting LAMP-2A in proteoliposomes in the presence of hsc70 is sufficient to mediate substrate translocation, although understandably at a lower efficiency than lysosomes (Cuervo AM and Dice JF, unpublished).…”

“…Lastly, it is possible that in other tumors, part of the negative consequences of CMA blockage are due to reduced quality control. While in many cancer cell types, prolonged blockage of CMA elicits upregulation of the ubiquitin proteasome system (UPS), thus preventing accumulation of damaged substrates normally degraded by CMA [35], in other types of cancers, accumulation of oxidized and misfolded proteins has been proposed to underlie the toxic effect of CMA blockage [23,64]. The upregulated CMA in these latter cells helps to ameliorate intracellular stress and promotes the activation of oncogenic survival pathways [23].…”

“…While in many cancer cell types, prolonged blockage of CMA elicits upregulation of the ubiquitin proteasome system (UPS), thus preventing accumulation of damaged substrates normally degraded by CMA [35], in other types of cancers, accumulation of oxidized and misfolded proteins has been proposed to underlie the toxic effect of CMA blockage [23,64]. The upregulated CMA in these latter cells helps to ameliorate intracellular stress and promotes the activation of oncogenic survival pathways [23]. The mechanism behind induction of CMA in tumorigenesis is still unclear, although it is tempting to postulate that microRNA deregulation may underlie the cancer-related increase in LAMP-2A expression as seen in the aberrant microRNA-mediated regulation of CMA components in neurodegeneration [60].…”

Dysregulation of autophagy and mitochondrial function in Parkinson’s disease

“…Notably, this motif is a pattern recognition motif associated with the hydrophobicity and charge of amino acid residues, rather than 100 % compliance with specific amino acid residues [26]. Interestingly, post-translational modification could perfect some KFERQ-similar motif for CMA through changing the hydrophobicity and charge of amino acid residues [27]. Briefly, CMA can be divided into four main steps: recognition, unfolding, translocation and degradation [28].…”