Therapeutic targeting of nuclear receptor corepressor misfolding in acute promyelocytic leukemia cells with genistein

Ng, Angela Ping Ping; Nin, Dawn Sijin; Fong, Jek Howe; Venkataraman, Divya; Chen, Chien-Shing; Khan, Matiullah

doi:10.1158/1535-7163.mct-06-0705

Cited by 25 publications

(34 citation statements)

References 33 publications

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“…3B). Apparently, the stabilization of N-CoR protein by curcumin was mediated by an inhibition of N-CoR degradation rather than an inhibition of N-CoR misfolding as observed previously with genistein (16). Consistent with this idea, relative level of detergent-insoluble N-CoR protein in NB4 cells or 293T cells overexpressing N-CoR was increased after curcumin treatment while there was hardly any change in the level of detergent-soluble N-CoR protein ( Fig.…”

Section: Selective Inhibition Of Growth Of Apl Cells By Curcuminsupporting

confidence: 84%

“…In our initial screening of selected compounds on APL-derived cells, we identified genistein and curcumin as potent inhibitors of growth of multiple APL-derived cells. The therapeutic effect of genistein and its underlying molecular mechanism of action have been documented previously (16). Here, we report that curcumin, a natural component of turmeric that has previously been shown to rescue the native conformation of several misfolded proteins such as the amyloid b (Ab), mutated cystic fibrosis transmembrane conductance regulator (CFTR), and truncated myelin protein zero (MPZ; refs.…”

Section: Introductionmentioning

confidence: 96%

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

Chng

Khan

2011

Molecular Cancer Research

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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.

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Section: Selective Inhibition Of Growth Of Apl Cells By Curcuminsupporting

confidence: 84%

Section: Introductionmentioning

confidence: 96%

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

Chng

Khan

2011

Molecular Cancer Research

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“…It was later identified as a Ski interacting protein in yeast two-hybrid assay [10] and was also demonstrated to have an essential role in the transcriptional repression of the tumor suppressors Mad and Rb [11], [12]. Our laboratory later reported that abrogation of N-CoR-mediated transcriptional repression due to a misfolded conformation dependent loss (MCDL) of N-CoR protein was associated with the differentiation arrest of leukemic cells in Acute Promyelocytic Leukemia (APL) [13], [14], [15]. Recently, N-CoR was also reported to be essential for the differentiation of erythroid cells [16].…”

Section: Introductionmentioning

confidence: 99%

Role of Misfolded N-CoR Mediated Transcriptional Deregulation of Flt3 in Acute Monocytic Leukemia (AML)-M5 Subtype

Nin

Kok

et al. 2012

PLoS ONE

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The nuclear receptor co-repressor (N-CoR) is a key component of the generic multi-protein complex involved in transcriptional control. Flt3, a key regulator of hematopoietic cell growth, is frequently deregulated in AML (acute myeloid leukemia). Here, we report that loss of N-CoR-mediated transcriptional control of Flt3 due to misfolding, contributes to malignant growth in AML of the M5 subtype (AML-M5). An analysis of hematopoietic genes in AML cells led to the identification of Flt3 as a transcriptional target of N-CoR. Flt3 level was inversely related to N-CoR status in various leukemia cells. N-CoR was associated with the Flt3 promoter in-vivo, and a reporter driven by the Flt3 promoter was effectively repressed by N-CoR. Blocking N-CoR loss with Genistein; an inhibitor of N-CoR misfolding, significantly down-regulated Flt3 levels regardless of the Flt3 receptor mutational status and promoted the differentiation of AML-M5 cells. While stimulation of the Flt3 receptor with the Flt3 ligand triggered N-CoR loss, Flt3 antibody mediated blockade of Flt3 ligand-receptor binding led to N-CoR stabilization. Genetic ablation of N-CoR potentiated Flt3 ligand induced proliferation of BA/F3 cells. These findings suggest that N-CoR-induced repression of Flt3 might be crucial for limiting the contribution of the Flt3 signaling pathway on the growth potential of leukemic cells and its deregulation due to N-CoR loss in AML-M5, could contribute to malignant growth by conferring a proliferative advantage to the leukemic blasts. Therapeutic restoration of N-CoR function could thus be a useful approach in restricting the contribution of the Flt3 signaling pathway in AML-M5 pathogenesis.

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“…Genistein (4 0 ,5,7-trihydroxy isoflavone), a natural isoflavone compound found in soy products, inhibits activation of protein tyrosine kinases and exhibits numerous effects on cell functions. For example, this compound inhibited tumor cell proliferation and metastasis, induced tumor cell differentiation, triggered cell cycle arrest at G 2 /M phase and apoptosis in some cell types, and blocked apoptosis under other circumstances [18][19][20][21][22][23][24][25][26]. Other evidence indicated that isoflavone consumption might be associated with an increased risk of HCC in women.…”

Section: Introductionmentioning

confidence: 99%

Genistein sensitizes human hepatocellular carcinoma cells to TRAIL-mediated apoptosis by enhancing Bid cleavage

et al. 2009

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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor superfamily, and it has been shown that many human cancer cell lines are refractory to TRAIL-induced cell death. However, the molecular mechanisms underlying resistance are unclear. In this study, we show that TRAIL resistance is reversed in human hepatoma cells by genistein, an isoflavone found in soy products. Synergistic induction of apoptosis in cells treated with genistein plus TRAIL was associated with cleavage of Bid, a proapoptotic BH3-only protein. Silencing of Bid expression reduced decreases in mitochondrial membrane potential and reduced apoptosis in cells treated with genistein and TRAIL, confirming that Bid cleavage is required for the response. Pretreatment with caspase-3 and caspase-8 inhibitors reduced cotreatment-induced apoptosis. However, treatment with TRAIL alone induced caspase-8 activity that was not different than TRAIL plus genistein; both effectively induced Bid cleavage. These data suggest that genistein abolishes resistance to the Bid cleavage of TRAIL, and that genistein does not interfere with signals upstream of Bid in hepatoma cells.

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Therapeutic targeting of nuclear receptor corepressor misfolding in acute promyelocytic leukemia cells with genistein

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

Cited by 25 publications

References 33 publications

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

Role of Misfolded N-CoR Mediated Transcriptional Deregulation of Flt3 in Acute Monocytic Leukemia (AML)-M5 Subtype

Genistein sensitizes human hepatocellular carcinoma cells to TRAIL-mediated apoptosis by enhancing Bid cleavage

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