BRD4 inhibition promotes TRAIL-induced apoptosis by suppressing the transcriptional activity of NF-κB in NSCLC

Numerous studies have indicated that tumor necrosis factor-alpha (TNF-α) could induce cancer cell survival and metastasis via activation of transcriptional activity of NF-κB and AP-1. Therefore, the inhibition of TNF-α-induced NF-κB and AP-1 activity has been considered in the search for drugs that could effectively treat cancer. Dicentrine, an aporphinic alkaloid, exerts anti-inflammatory and anticancer activities. Therefore, we investigated the effects of dicentrine on TNF-α-induced tumor progression in A549 lung adenocarcinoma cells. Our results demonstrated that dicentrine effectively sensitizes TNF-α-induced apoptosis in A549 cells when compared with dicentrine alone. In addition, dicentrine increases caspase-8, -9, -3, and poly (ADP-ribose) polymerase (PARP) activities by upregulating the death-inducing signaling complex and by inhibiting the expression of antiapoptotic proteins including cIAP2, cFLIP, and Bcl-XL. Furthermore, dicentrine inhibits the TNF-α-induced A549 cells invasion and migration. This inhibition is correlated with the suppression of invasive proteins in the presence of dicentrine. Moreover, dicentrine significantly blockes TNF-α-activated TAK1, p38, JNK, and Akt, leading to reduced levels of the transcriptional activity of NF-κB and AP-1. Taken together, our results suggest that dicentrine could enhance TNF-α-induced A549 cell death by inducing apoptosis and reducing cell invasion due to, at least in part, the suppression of TAK-1, MAPK, Akt, AP-1, and NF-κB signaling pathways.

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TNFR1-dependent cell death drives inflammation in Sharpin-deficient mice

eLife ◽

10.7554/elife.03464 ◽

2014 ◽

Vol 3 ◽

Cited By ~ 145

Author(s):

James A Rickard ◽

Holly Anderton ◽

Nima Etemadi ◽

Ueli Nachbur ◽

Maurice Darding ◽

...

Keyword(s):

Cell Death ◽

Transcriptional Activity ◽

Peyer's Patches ◽

Peyer’S Patches ◽

Inflammatory Phenotype ◽

Dependent Cell ◽

Perinatal Lethality ◽

Induced Apoptosis ◽

Deficient Mice

SHARPIN regulates immune signaling and contributes to full transcriptional activity and prevention of cell death in response to TNF in vitro. The inactivating mouse Sharpin cpdm mutation causes TNF-dependent multi-organ inflammation, characterized by dermatitis, liver inflammation, splenomegaly, and loss of Peyer's patches. TNF-dependent cell death has been proposed to cause the inflammatory phenotype and consistent with this we show Tnfr1, but not Tnfr2, deficiency suppresses the phenotype (and it does so more efficiently than Il1r1 loss). TNFR1-induced apoptosis can proceed through caspase-8 and BID, but reduction in or loss of these players generally did not suppress inflammation, although Casp8 heterozygosity significantly delayed dermatitis. Ripk3 or Mlkl deficiency partially ameliorated the multi-organ phenotype, and combined Ripk3 deletion and Casp8 heterozygosity almost completely suppressed it, even restoring Peyer's patches. Unexpectedly, Sharpin, Ripk3 and Casp8 triple deficiency caused perinatal lethality. These results provide unexpected insights into the developmental importance of SHARPIN.

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Myc Targets Cks1 To Provoke Proliferation and Lymphomagenesis.

Blood ◽

10.1182/blood.v106.11.2618.2618 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2618-2618

Author(s):

Ulrich Keller ◽

Jennifer B. Old ◽

Jonas Nilsson ◽

Lisa Nilsson ◽

Kirsteen Maclean ◽

...

Keyword(s):

Cell Proliferation ◽

B Cells ◽

Burkitt Lymphoma ◽

Poor Prognosis ◽

Transcriptional Activity ◽

Kinase Inhibitor ◽

Ex Vivo ◽

Cyclin Dependent Kinase ◽

Cyclin Dependent Kinase Inhibitor ◽

Induced Apoptosis

Abstract Reduced levels of the cyclin dependent kinase inhibitor p27Kip1 connote poor prognosis in cancer. In human Burkitt lymphoma, and in pre-cancerous B cells and lymphomas arising in Eμ-Myc transgenic mice, p27Kip1 expression is markedly reduced. Furthermore, the Cks1 component of the SCFSkp2 complex that is necessary for p27Kip1 ubiquitylation and degradation, and to a lesser extent Skp2, are induced by Myc ex vivo and in Eμ-Myc B-cells and lymphomas, and up-regulation of CKS1 and SKP2 are hallmarks of Burkitt lymphoma. While loss of Skp2 has rather modest effects, the deletion of Cks1 in Eμ-Myc B-cells elevates p27Kip1 levels, reduces proliferation and delays lymphoma development. In contrast, Myc-induced apoptosis and transcriptional activity are not affected by Cks1 (or Skp2) loss. Therefore, Myc accelerates cell proliferation and promotes tumorigenesis through its ability to selectively induce Cks1.

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Triptolide Synergistically Enhances Temozolomide-Induced Apoptosis and Potentiates Inhibition of NF-κB Signaling in Glioma Initiating Cells

The American Journal of Chinese Medicine ◽

10.1142/s0192415x14500323 ◽

2014 ◽

Vol 42 (02) ◽

pp. 485-503 ◽

Cited By ~ 21

Author(s):

Ke Sai ◽

Wen-Yu Li ◽

Yin-Sheng Chen ◽

Jian Wang ◽

Su Guan ◽

...

Keyword(s):

Western Blot ◽

Transcriptional Activity ◽

Combined Treatment ◽

Acquired Resistance ◽

Luciferase Assay ◽

Solid Cancer ◽

Tumor Sphere ◽

Glioma Initiating Cells ◽

Induced Apoptosis ◽

Sphere Formation

Glioblastoma multiforme (GBM) is a lethal solid cancer in adults. Temozolomide (TMZ) is a first-line chemotherapeutic agent but the efficacy is limited by intrinsic and acquired resistance in GBM. Triptolide (TPL), a derivative from traditional Chinese medicine, demonstrated anti-tumor activity. In this study, we explored the interaction of TPL and TMZ in glioma-initiating cells (GICs) and the potential mechanism. A GIC line (GIC-1) was successfully established. Cell viability of GIC-1 after treatment was measured using a CCK-8 assay. The interaction between TPL and TMZ was calculated from Chou–Talalay equations and isobologram. Self-renewal was evaluated with tumor sphere formation assay. Apoptosis was assessed with flow cytometry and western blot. Luciferase assay was employed to measure NF-κB transcriptional activity. The expression of NF-κB downstream genes, NF-κB nuclear translocalization and phoshorylation of IκBα and p65 were evaluated using western blot. We found that GIC-1 cells were resistant to TMZ, with the expected IC50 of 705.7 μmol/L. Co-treatment with TPL yielded a more than three-fold dose reduction of TMZ. TPL significantly increased the percentage of apoptotic cells and suppressed the tumor sphere formation when combined with TMZ. Phosphorylation of IκBα and p65 coupled with NF-κB nuclear translocalization were notably inhibited after a combined treatment. Co-incubation synergistically repressed NF-κB transcriptional activity and downstream gene expression. TPL sensitizes GICs to TMZ by synergistically enhancing apoptosis, which is likely resulting from the augmented repression of NF-κB signaling. TPL is therefore a potential chemosensitizer in the treatment of GBM.

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WITHDRAWN:Mitochondrial targeting of HIF-1α inhibits hypoxia-induced apoptosis independently of its transcriptional activity

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2018.04.568 ◽

2018 ◽

Cited By ~ 1

Author(s):

Hong-Sheng Li ◽

Yan-Ni Zhou ◽

Lu Li ◽

Sheng-Fu Li ◽

Dan Long ◽

...

Keyword(s):

Transcriptional Activity ◽

Induced Apoptosis

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GRK5 is an Essential Co-repressor for Cardiac Mineralocorticoid Receptor Antagonism induced by Finerenone but not Eplerenone

10.20944/preprints202009.0374.v1 ◽

2020 ◽

Author(s):

Victoria L. Desimine ◽

Jennifer Ghandour ◽

Natalie Cora ◽

Celina M. Pollard ◽

Rachel Valiente ◽

...

Keyword(s):

Mineralocorticoid Receptor ◽

Transcriptional Activity ◽

Ventricular Myocytes ◽

Neonatal Rat ◽

Human Heart Failure ◽

Cardiac Mr ◽

Inverse Agonism ◽

Mineralocorticoid Receptor Antagonism ◽

H9c2 Cardiomyocytes ◽

Induced Apoptosis

Background: In the heart, aldosterone (Aldo) binds the mineralocorticoid receptor (MR) to exert damaging, adverse remodeling-promoting effects. We recently showed that G protein-coupled receptor (GPCR)-kinase (GRK)-5 blocks the cardiac MR by directly phosphorylating it, thereby repressing its transcriptional activity. MR antagonist (MRA) drugs block the cardiac MR reducing morbidity and mortality of advanced human heart failure. Non-steroidal MRAs, such as finerenone, may provide better cardio-protection against Aldo than classic, steroidal MRAs, like spironolactone and eplerenone. Herein, we sought to investigate potential differences between finerenone and eplerenone at engaging GRK5-dependent cardiac MR phosphorylation and subsequent blockade. Methods: We used the cardiomyocyte cell line H9c2 and neonatal rat ventricular myocytes (NRVMs). Results: GRK5 phosphorylates the MR in H9c2 cardiomyocytes in response to finerenone but not to eplerenone. Unlike eplerenone, finerenone alone potently and efficiently suppresses cardiac MR transcriptional activity, thus displaying inverse agonism. GRK5 is necessary for finerenone`s inverse agonism, since GRK5 genetic deletion renders finerenone incapable of blocking cardiac MR transcriptional activity. Eplerenone alone does not fully suppress cardiac MR basal activity regardless of GRK5 expression levels. Finally in NRVMs, GRK5 is necessary for the anti-apoptotic and anti-fibrotic effects of both finerenone and eplerenone against Aldo, as well as for the higher efficacy and potency of finerenone at blocking Aldo-induced apoptosis and fibrosis. Conclusions: Finerenone, but not eplerenone, induces GRK5-dependent cardiac MR inhibition, which underlies, at least in part, its higher potency and efficacy, compared to eplerenone, as an MRA in the heart. GRK5 acts as a co-repressor of the cardiac MR and is essential for efficient MR antagonism in the myocardium.

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Tissue-specific regulation of p53 by PKM2 is redox dependent and provides a therapeutic target for anthracycline-induced cardiotoxicity

Science Translational Medicine ◽

10.1126/scitranslmed.aau8866 ◽

2019 ◽

Vol 11 (478) ◽

pp. eaau8866 ◽

Cited By ~ 13

Author(s):

Bruno Saleme ◽

Vikram Gurtu ◽

Yongneng Zhang ◽

Adam Kinnaird ◽

Aristeidis E. Boukouris ◽

...

Keyword(s):

Heart Failure ◽

Oxidation State ◽

Transcriptional Activity ◽

Tumor Regression ◽

Clinical Problem ◽

Redox Status ◽

Tissue Specific ◽

Targeting Therapy ◽

Specific Regulation ◽

Induced Apoptosis

Chemotherapy-induced cardiotoxicity (CIC) is a common clinical problem that compromises effective anticancer therapies. Many chemotherapeutics (including anthracyclines, such as doxorubicin) induce the proapoptotic transcription factor p53 in the tumor and nonspecifically in the heart, promoting heart failure. Although inhibition of p53 shows benefit in preclinical heart failure models, it would not be an attractive adjuvant therapy for CIC, because it would prevent tumor regression. A p53-targeting therapy that would decrease chemotherapy-induced apoptosis in the myocardium and, at the same time, enhance apoptosis in the tumor would be ideal. Here, we propose that differences in oxygen tension between the myocardium and the tumor could provide a platform for redox-dependent tissue-specific therapies. We show by coimmunoprecipitation and mass spectrometry that the redox-regulated pyruvate kinase muscle 2 (PKM2) directly binds with p53 and that the redox status of cysteine-423 of tetrameric (but not monomeric) PKM2 is critical for the differential regulation of p53 transcriptional activity. Tetrameric PKM2 suppresses p53 transcriptional activity and apoptosis in a high oxidation state but enhances them in a low oxidation one. We show that the oxidation state (along with cysteine-423 oxidation) is higher in the heart compared to the tumor of the same animal. Treatment with TEPP-46 (a compound that stabilizes tetrameric PKM2) suppressed doxorubicin-induced cardiomyocyte apoptosis, preventing cardiac dysfunction, but enhanced cancer cell apoptosis and tumor regression in the same animals in lung cancer models. Thus, our work suggests that redox-dependent differences in common proteins expressed in the myocardium and tumor can be exploited therapeutically for tissue selectivity in CIC.

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