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.
Highlights
Transcriptional factors and their cognate co-factors are the major regulators of development of epithelial cells and are among the most frequent targets of oncogenic insult in various human malignancies including Lung cancer [1,2,3,4]
Analysis of Nuclear receptor co-repressor (N-CoR) status in various lung cancer cells revealed an apparent loss of N-CoR at protein level in multiple tumor cell lines derived from non-small cell lung cancer (NSCLC), but not in DMS-79; a cell line derived from small-cell lung cancer (SCLC) (Fig. 1A, Supporting Information S1)
A similar pattern of N-CoR loss was observed in normal small airway epithelial cells (SAEC) after treatment with nicotine, the carcinogenic agent widely linked to Lung cancer (Fig. 1B)
Summary
Transcriptional factors and their cognate co-factors are the major regulators of development of epithelial cells and are among the most frequent targets of oncogenic insult in various human malignancies including Lung cancer [1,2,3,4]. Some of the transcription factors and co-factors that were initially identified as the regulators of normal hematopoiesis were found to be involved in the regulation of normal growth and development of lung epithelial cells [2,3,4]. These finding suggested that considerable overlapping might exist in the mechanism underlying the hematological malignancies and Lung Cancer. Based on currently known histo-pathological criteria, lung cancer is broadly categorized into two major subtypes: non-small-cell lung cancer [9,10]
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