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.