APL (acute promyelocytic leukemia) is characterized by accumulation of apoptosis-resistant immature promyelocytic cells in the bone marrow and peripheral blood. We have shown that endoplasmic reticulum-associated degradation (ERAD) and protease-mediated degradation of misfolded nuclear receptor co-repressor (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. Based on 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 curcumin-induced apoptosis of APL cells was triggered by an amplification of endoplasmic reticulum (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 PERK and eIF2α, and up-regulation of CHOP and GADD34, the principal mediators of pro-apoptotic 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.
- Received December 2, 2010.
- Revision received May 4, 2011.
- Accepted May 16, 2011.
- Copyright © 2011, American Association for Cancer Research.