title: 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.
authors.affiliation: Cancer Science Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Azhar Bin
authors.initials: AB
authors.lastname: Ali
authors.forename: Dawn Sijin
authors.initials: DS
authors.lastname: Nin
authors.forename: John
authors.initials: J
authors.lastname: Tam
authors.forename: Matiullah
authors.initials: M
authors.lastname: Khan
mesh_terms: D001343:Autophagy / Q000502:physiology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D056970:Co-Repressor Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D018832:Molecular Chaperones / Q000378:metabolism*; D017510:Protein Folding; D060888:Real-Time Polymerase Chain Reaction; D012995:Solubility; D014407:Tumor Cells, Cultured
chemical_list: D056970:Co-Repressor Proteins; D018832:Molecular Chaperones