Curcumin Sensitizes Acute Promyelocytic Leukemia Cells to Unfolded Protein Response-Induced Apoptosis by Blocking the Loss of Misfolded N-CoR Protein
Curcumin Sensitizes Acute Promyelocytic Leukemia Cells to Unfolded Protein Response-Induced Apoptosis by Blocking the Loss of Misfolded N-CoR Protein
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DOI：
10.1158/1541-7786.mcr-10-0545
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发表时间：
2011-07-01
影响因子：
5.2
通讯作者：
Khan, Matiullah
中科院分区：
文献类型：
--
作者：
Ng, Angela Ping Ping;Chng, Wee Joo;Khan, Matiullah
急性早幼粒细胞白血病（APL）的特征是在骨髓和外周血中积累的抗凋亡的未成熟早幼粒细胞。我们已经证明，内质网（ER）相关的降解（ERAD）和蛋白酶介导的降解错误折叠的核受体辅阻遏物（N-CoR）赋予抵抗未折叠蛋白反应（UPR）诱导的APL细胞凋亡。这些研究结果表明，治疗抑制N-CoR错误折叠或降解可能会促进APL细胞的生长停滞，使他们敏感的UPR诱导的细胞凋亡。在此假设的基础上，我们测试了几种已知的蛋白质构象修饰剂对APL细胞的生长和存活的影响，并确定了姜黄素，姜黄的天然成分，作为APL细胞的有效生长抑制剂。姜黄素选择性地抑制APL原代和继发性白血病细胞的生长并促进其凋亡。姜黄素诱导的APL细胞凋亡是由内质网应激的放大触发的，可能是由于错误折叠的N-CoR蛋白在内质网中的积累。姜黄素通过阻断其ERAD和蛋白酶介导的降解，促进了这种异常磷酸化的错误折叠的N-CoR蛋白的净积累，然后导致激活UPR诱导的APL细胞凋亡。姜黄素激活UPR表现为蛋白激酶RNA样内质网激酶（PERK）和真核翻译起始因子2 α（eIF 2 α）的磷酸化，以及C/EBP同源蛋白（CHOP）和GADD 34（促凋亡UPR的主要介质）的上调。这些发现确定了姜黄素在APL中的治疗潜力，并进一步确立了错误折叠的N-CoR蛋白作为APL中有吸引力的分子靶点的基本原理。Mol Cancer Res; 9（7）; 878-88.（C）2011年《非洲标准化评论》。
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 curcumin-induced 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 (eIF2 alpha), 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. (C)2011 AACR.