Curcumin, a Major Constituent of Turmeric, Corrects Cystic Fibrosis Defects

Egan, Marie E.; Pearson, Marilyn; Weiner, Scott A; Rajendran, V.; Rubin, Daniel B.; Glöckner-Pagel, Judith; Canny, Susan; Du, Kai; Lukacs, Gergely L.; Caplan, Michael J.

doi:10.1126/science.1093941

Cited by 517 publications

(420 citation statements)

References 25 publications

Supporting

Mentioning

407

Contrasting

Unclassified

Order By: Relevance

“…Curcumin was selected in our initial screening assay against APL-derived cells for its potent inhibitory effect on the misfolding of Ab, CFTR, and MPZ proteins (17)(18)(19). Although curcumin was as effective as genistein in stabilizing the full-length N-CoR protein, the N-CoR stabilization by curcumin did not result from an inhibition of N-CoR misfolding as observed with genistein.…”

Section: Discussionmentioning

confidence: 99%

“…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. [17][18][19], selectively sensitizes APL cells to UPR-induced apoptosis by promoting the net accumulation of misfolded N-CoR protein in the ER.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

View full text Add to dashboard Cite

show abstract

“…Curcumin (a component of the spice tumeric) has been shown to correct mutant CFTR processing in the cell in some studies [90] but not others [91], and results in mouse models of this disease have remained variable [92]. Other molecules in the sarcoplasmic reticulum Ca 2+ -ATPase-(SERCA) pump family also show some promise as therapeutic targets to correct defective CFTR function.…”

Section: Restoration Of Cftr Expression or Functionmentioning

confidence: 99%

Airway epithelial control of Pseudomonas aeruginosa infection in cystic fibrosis

Campodónico

Gadjeva

Paradis-Bleau

et al. 2008

Trends in Molecular Medicine

View full text Add to dashboard Cite

Defective expression or function of the cystic fibrosis transmembrane conductance regulator (CFTR) underlies the hypersusceptibility of cystic fibrosis (CF) patients to chronic airway infections, particularly with Pseudomonas aeruginosa. CFTR is involved in the specific recognition of P. aeruginosa, thereby contributing to effective innate immunity and proper hydration of the airway surface layer (ASL). In CF, the airway epithelium fails to initiate an appropriate innate immune response, allowing the microbe to bind to mucus plugs that are then not properly cleared because of the dehydrated ASL. Recent studies have identified numerous CFTR-dependent factors that are recruited to the epithelial plasma membrane in response to infection and that are needed for bacterial clearance, a process that is defective in CF patients hypersusceptible to infection with this organism. Pseudomonas aeruginosa in cystic fibrosisCystic fibrosis (CF) is unique among human genetic disorders in that mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a protein whose primary function described to date has been to regulate conductance of ions in and out of cells and intracellular vacuoles, lead to hypersusceptibility to chronic lung infection. Human diseases wherein individuals homozygous for mutant genes are predisposed to infections serve as a firm foundation for understanding the molecular, cellular, physiologic and immunologic aspects of normal and compromised resistance to infection. CF is not just a prime example of how we can learn about normal and pathologic states; it could, in fact, be the only known human genetically determined disease wherein infection with a single pathogen -Pseudomonas aeruginosa -drives the vast majority of morbidity, clinical deterioration and ultimately life-shortening mortality encountered in this disease. In humans with significant compromises to their immune system, such as advanced AIDS, we would normally expect to see a plethora of pathogens take advantage of this debilitated state, but this is not the case in CF.CF is characterized by the emergence and persistence of (and, ultimately, the inability to clear) chronic infection with a variant of P. aeruginosa (mucoid P. aeruginosa) that overproduces a surface polysaccharide known as alginate. The organism undergoes other significant genetic adaptations and selections within the CF lung, and it is the emergence of mucoid P. aeruginosa that is the primary determinant of the clinical course of this disease [1,2]. In those individuals with either an uncommon but fortuitous protective immune response to specific P. aeruginosa antigens [3,4] Histopathologic basis for defining relevant interactions between P.aeruginosa and the CF airway epitheliumAlthough CF is a multisystem disease characterized by GI and nutritional abnormalities, salt loss syndromes and male urogenital abnormalities, the major clinical problem for CF patients is chronic sinopulmonary disease. Therefore, relying on observations made fr...

show abstract

“…Drug-induced depletion of ER Ca 2؉ stores does not rescue hNa v 1.1-M1841T It has been shown that depletion of ER Ca 2ϩ stores by inhibitors of Ca 2ϩ pumps, such as curcumin and thapsigargin, can rescue some trafficking-defective mutants (Cobbold et al, 2003;Egan et al, 2004).…”

Section: Other Molecular Interactions Can Rescue Hna V 11-m1841tmentioning

confidence: 99%

Modulatory Proteins Can Rescue a Trafficking Defective Epileptogenic Na_v1.1 Na⁺Channel Mutant

Rusconi¹,

Scalmani²,

Cassulini³

et al. 2007

J. Neurosci.

108

110

View full text Add to dashboard Cite

Familial epilepsies are often caused by mutations of voltage-gated Na ϩ channels, but correlation genotype-phenotype is not yet clear. In particular, the cause of phenotypic variability observed in some epileptic families is unclear. We studied Na v 1.1 (SCN1A) Na ϩ channel ␣ subunit M1841T mutation, identified in a family characterized by a particularly large phenotypic spectrum. The mutant is a loss of function because when expressed alone, the current was no greater than background. Function was restored by incubation at temperature Ͻ30°C, showing that the mutant is trafficking defective, thus far the first case among neuronal Na ϩ channels. Importantly, also molecular interactions with modulatory proteins or drugs were able to rescue the mutant. Protein-protein interactions may modulate the effect of the mutation in vivo and thus phenotype; variability in their strength may be one of the causes of phenotypic variability in familial epilepsy. Interacting drugs may be used to rescue the mutant in vivo.

show abstract

Curcumin, a Major Constituent of Turmeric, Corrects Cystic Fibrosis Defects

Cited by 517 publications

References 25 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

Airway epithelial control of Pseudomonas aeruginosa infection in cystic fibrosis

Modulatory Proteins Can Rescue a Trafficking Defective Epileptogenic Na_v1.1 Na⁺Channel Mutant

Contact Info

Product

Resources

About

Curcumin, a Major Constituent of Turmeric, Corrects Cystic Fibrosis Defects

Cited by 517 publications

References 25 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

Airway epithelial control of Pseudomonas aeruginosa infection in cystic fibrosis

Modulatory Proteins Can Rescue a Trafficking Defective Epileptogenic Nav1.1 Na+Channel Mutant

Contact Info

Product

Resources

About

Modulatory Proteins Can Rescue a Trafficking Defective Epileptogenic Na_v1.1 Na⁺Channel Mutant