Curcumin Sensitizes Acute Promyelocytic Leukemia Cells to Unfolded Protein Response–Induced Apoptosis by Blocking the Loss of Misfolded N-CoR Protein

Abstract

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.

Akt-Induced Phosphorylation of N-CoR at Serine 1450 Contributes to Its Misfolded Conformational Dependent Loss (MCDL) in Acute Myeloid Leukemia of the M5 Subtype

“…The loss of N-CoR observed in AML-M5 cells largely resembled the pattern of N-CoR loss previously reported by us in APL [12], [13], [39]. The N-CoR loss in APL was essentially triggered by PML-RARα-induced phosphorylation of N-CoR, altering its conformation to an extent where it became unstable and eventually degraded by a protease-based protein quality control mechanism.…”

Spices for Prevention and Treatment of Cancers

“…In addition, curcumin could inhibit the growth and promote apoptosis of leukemic cells which were derived from acute promyelocytic leukemia. The apoptosis induced by curcumin was through an amplification of endoplasmic reticulum (ER) stress, which possibly resulted from the accumulation of misfolded nuclear receptor corepressor protein in the ER [83]. In another study, in Burkitt’s lymphoma cell lines, ionizing radiation-induced apoptosis and G 2 /M phase arrest were increased by pretreatment of curcumin through NF-κB pathway [84].…”

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“…The 5-year Perspective Aberrant RNA splicing and mutations in spliceosome complex in acute myeloid leukemia overall survival rate is about 20% in adult AML patients (2,3). These poor outcomes highlight the unmet need for a better understanding of leukemogensis and novel, targeted therapies to replace chemotherapy, which has not been changed for more than four decades (4)(5)(6)(7).…”