role of chaperone mediated autophagy (cma) in the degradation of misfolded n-cor protein in non-small cell lung cancer (nsclc) cells伴侣蛋白介导的自噬的作用(cma)的降解错误折叠n-cor蛋白在非小细胞肺癌(nsclc)细胞.pdfVIP

Role of Chaperone Mediated Autophagy (CMA) in the Degradation of Misfolded N-CoR Protein in Non-Small Cell Lung Cancer (NSCLC) Cells 1 1,2 3,4 1,2 Azhar Bin Ali , Dawn Sijin Nin , John Tam , Matiullah Khan * 1 Cancer Science Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 2 Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 3 Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 4 Departments of Cardiac, Thoracic Vascular Surgery, National University Hospital, Singapore, Singapore 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