We have recently reported that accumulation of misfolded nuclear hormone receptor corepressor (N-CoR) as insoluble protein aggregates in acute promyelocytic leukemia (APL) cells induces endoplasmic reticulum (ER) stress and activates unfolded protein response (UPR). Although accumulation of misfolded proteins is known to trigger UPR-induced cytotoxic cell death in several neurodegenerative disorders, APL cells are notably resistant to UPR-induced apoptosis. The molecular basis for the paradoxical response of APL cells to UPR is not known. Here, we report that a glycoprotease, selectively

We have recently reported that PML-RAR -induced mis-

Acute promyelocytic leukemia (APL) is characterized by accumulation of apoptosis-resistant immature promyelocytic cells in the bone marrow and peripheral blood. We have shown that endoplasmic reticulum (ER)-associated degradation (ERAD) and protease-mediated degradation of misfolded nuclear receptor corepressor (N-CoR) confer resistance to unfolded protein response (UPR)-induced apoptosis in APL. These findings suggest that therapeutic inhibition of N-CoR misfolding or degradation may promote growth arrest in APL cells by sensitizing them to UPR-induced apoptosis. On the basis of this hypothesis, we tested the effects of several known protein conformation-modifying agents on the growth and survival of APL cells and identified curcumin, a natural component of turmeric, as a potent growth inhibitor of APL cells. Curcumin selectively inhibited the growth and promoted apoptosis in both primary and secondary leukemic cells derived from APL. The curcumininduced apoptosis of APL cells was triggered by an amplification of ER stress, possibly from the accumulation of misfolded N-CoR protein in the ER. Curcumin promoted this net accumulation of aberrantly phosphorylated misfolded N-CoR protein by blocking its ERAD and protease-mediated degradation, which then led to the activation of UPR-induced apoptosis in APL cells. The activation of UPR by curcumin was manifested by phosphorylation of protein kinase RNA-like endoplasmic reticulum kinase (PERK) and eukaryotic translation initiation factor 2 alpha (eIF2a), and upregulation of C/EBP homologous protein (CHOP) and GADD34, the principal mediators of proapoptotic UPR. These findings identify the therapeutic potential of curcumin in APL and further establish the rationale of misfolded N-CoR protein as an attractive molecular target in APL. Mol Cancer Res; 9(7); 878-88. Ó2011 AACR.