Cleavage of Misfolded Nuclear Receptor Corepressor Confers Resistance to Unfolded Protein Response–Induced Apoptosis

Ng, Angela Ping Ping; Fong, Jek Howe; Nin, Dawn Sijin; Hirpara, Jayshree L.; Asou, Norio; Chen, Chien-Shing; Pervaiz, Shazib; Khan, Matiullah

doi:10.1158/0008-5472.can-06-0002

Cited by 21 publications

(44 citation statements)

References 42 publications

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“…The number of cells at S-phase was not significantly affected. vehicle or curcumin, as well as with AEBSF, a broadspectrum protease inhibitor that abrogated N-CoR cleavage in NB4 cells (4). Extract of curcumin-treated NB4 cells did not cleave Flag-tagged N-CoR protein as efficiently as extract of vehicle-treated NB4 cells.…”

Section: Selective Inhibition Of Growth Of Apl Cells By Curcuminmentioning

confidence: 87%

“…We have previously shown how degradation of misfolded N-CoR protein led to the attenuation of ER stress and protected APL cells from UPR-induced apoptosis (4). On the basis of this finding, we hypothesized that amplification of ER stress due to curcumin-induced accumulation of misfolded N-CoR protein in the ER will eventually resensitize APL cells to UPR-induced apoptosis.…”

Section: Curcumin Activates Upr-induced Apoptosis In Apl Cellsmentioning

confidence: 94%

“…Although there is no dispute on the principal role of PML-RARa in the transformation of APL cells, the molecular mechanisms through which PML-RARa promotes transformation are still a matter of intense debate. We have shown that endoplasmic reticulum (ER)-associated degradation (ERAD) and protease-mediated degradation of misfolded nuclear receptor corepressor (N-CoR) plays a significant role in resistance of APL cells to unfolded protein response (UPR)-induced apoptosis (3,4). N-CoR, a key component of the generic corepressor protein complex involved in transcriptional control mediated by various transcription factors, was first identified as a corepressor of unliganded nuclear hormone receptors (5,6).…”

Section: Introductionmentioning

confidence: 99%

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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 Curcuminmentioning

confidence: 87%

Section: Curcumin Activates Upr-induced Apoptosis In Apl Cellsmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

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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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“…Proteolytic processing of PML-RAR by neutrophil elastase, proteinase 3, and cathepsin G, as well as cleavage of misfolded N-CoR by OGSEP, has been implicated in the pathogenesis of APL (12,29). Expression of some of these APL-specific proteases, such as OSGEP and cathepsin G, are indeed restricted to NB4 cells, as their expression was not detected in the non -APL cell line HL-60 (Supplementary Fig.…”

Section: Inhibition Of N-cor Cleavage By Genistein Is Mediated By Dowmentioning

confidence: 99%

“…We have shown that aberrant association of N-CoR with PML-RAR in the cytosol contributed to the misfolding of N-CoR protein (11,12). Therefore, we investigated whether genistein-induced inhibition of N-CoR misfolding results from a possible inhibition of N-CoR binding to PML-RAR in the cytosol.…”

Section: Genistein Inhibits the Binding Of N-cor To Pml-rar And Abrogmentioning

confidence: 99%

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

Nin²,

Fong³

et al. 2007

Molecular Cancer Therapeutics

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Curcumin Analogues with Potent and Selective Anti‐proliferative Activity on Acute Promyelocytic Leukemia: Involvement of Accumulated Misfolded Nuclear Receptor Co‐repressor (N‐CoR) Protein as a Basis for Selective Activity

Tan¹,

Koh²,

Ee³

et al. 2012

ChemMedChem

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Curcumin arrests the proliferation of acute promyelocytic leukemia (APL) cells by stabilizing the misfolded nuclear receptor co-repressor (N-CoR) protein, thereby sensitizing APL cells to apoptosis induced by the unfolded protein response. This phenomenon was attributed to inhibition of the proteasomal and protease-induced breakdown of misfolded N-CoR by curcumin. Curcumin is, however, a modest inhibitor and affected the viability of APL cells at micromolar concentrations. Modifying curcumin at its conjugated β-diketone linker and terminal phenyl rings yielded potent congeners with sub-micromolar growth inhibitory activities which selectively kill APL cells over non-APL leukemic and nonmalignant cells. Analogues with pronounced APL-selective anti-proliferative activities, as observed in representative dibenzylidenecyclohexanones and dibenzylidenecyclopentanones, strongly promoted the accumulation of misfolded and nonfunctional N-CoR at significantly lower concentrations than their growth inhibitory IC(50) values. These compounds also inhibited the human 20S proteasome in an enzyme-based assay, thus providing convincing support for the prevailing hypothesis that impeding the degradation of N-CoR is a key mechanistic event contributing to APL cell death.

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Cleavage of Misfolded Nuclear Receptor Corepressor Confers Resistance to Unfolded Protein Response–Induced Apoptosis

Cited by 21 publications

References 42 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

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

Curcumin Analogues with Potent and Selective Anti‐proliferative Activity on Acute Promyelocytic Leukemia: Involvement of Accumulated Misfolded Nuclear Receptor Co‐repressor (N‐CoR) Protein as a Basis for Selective Activity

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