Troglitazone-mediated sensitization to TRAIL-induced apoptosis is regulated by proteasome-dependent degradation of FLIP and ERK1/2-dependent phosphorylation of BAD

Grund, Kerstin; Ahmadi, Rezvan; Jung, Fortunata; Funke, Verena; Gdynia, Georg; Benner, Axel; Sykora, Jaromir; Walczak, Henning; Joos, Stefan; Felsberg, Jörg; Reifenberger, Guido; Wiestler, Otmar D.; Herold‐Mende, Christel; Roth, Wilfried

doi:10.4161/cbt.7.12.6966

Cited by 15 publications

(9 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been shown that either single or double phosphorylated Ser-112 and Ser-136 of Bad would inactivate its pro-apoptotic activity [31]. Indeed phosphorylation of Bad at ser-112 and/or ser-136 was responsible for cancer cells resistance to a number of therapeutic agents [25,44,45]. Our data, for the first time, showed that ABT-737 induced a concentration-dependent increase of Bad phosphorylation on both ser-136 and ser-112 (Fig.…”

Section: Discussionsupporting

confidence: 51%

Methylseleninic acid potentiates multiple types of cancer cells to ABT-737-induced apoptosis by targeting Mcl-1 and Bad

et al. 2011

View full text Add to dashboard Cite

ABT-737, a novel small molecule inhibitor of Bcl-2 family proteins, holds great promise to complement current cancer therapies. However many types of solid cancer cells are resistant to ABT-737. One practical approach to improve its therapeutic efficacy is to combine with the agents that can overcome such resistance to restore the sensitivity. In the present study, a second-generation selenium compound methylseleninic acid (MSeA) synergistically sensitized MDA-MB-231 human breast cancer cells, HT-29 human colon cancer cells and DU145 human prostate cancer cells to apoptosis induction by ABT-737, as evidenced by greater than additive enhancement of Annexin V/FITC positive (apoptotic) cells and activation of multiple caspases and PARP cleavage. Mechanistic investigation demonstrated that MSeA significantly decreased basal Mcl-1 expression and ABT-737-induced Mcl-1 expression. Knocking down of Mcl-1 with RNAi approach supported the functional significance of this molecular target. More importantly, we identified inactivation of Bad by phosphorylation on ser-136 and ser-112 as a novel mechanism involved in ABT-737 resistance, which can be overcome by combining with MSeA. In addition, we found that expression of Bax was required for the efficient execution of synergistic sensitization. Our findings, for the first time, provide a strong mechanistic rationale for developing MSeA as a novel sensitizing agent of ABT-737.

show abstract

Section: Discussionsupporting

confidence: 51%

Methylseleninic acid potentiates multiple types of cancer cells to ABT-737-induced apoptosis by targeting Mcl-1 and Bad

et al. 2011

View full text Add to dashboard Cite

show abstract

“…Moreover, suppression of ERK1/2 phosphorylation by an inhibitor of ERK1/2 and TRAIL enhanced TRAILinduced apoptosis and suppression of BAD phosphorylation. Consistent with our results, it has been reported that inactivated ERK1/2 enhances TRAIL-induced apoptosis in melanoma and glioblastoma cells through the inhibition of phosphorylated BAD [35,36]. The inactive form of BAD, phosphorylated at Ser-112 by ERK1/2, is sequestered in the cytosol bound to the 14-3-3 protein, thus freeing Bcl-XL and Bcl-2 to promote cell survival [37,38].…”

Section: Discussionsupporting

confidence: 93%

Elevated pressure enhanced TRAIL-induced apoptosis in hepatocellular carcinoma cells via ERK1/2-inactivation

Hong¹,

Lee²,

Kim³

et al. 2015

Cellular and Molecular Biology Letters

View full text Add to dashboard Cite

The high frequency of intrinsic resistance to TNF-related apoptosisinducing ligand (TRAIL) in tumor cell lines has necessitated the development of strategies to sensitize tumors to TRAIL-induced apoptosis. We previously showed that elevated pressure applied as a mechanical stressor enhanced TRAIL-mediated apoptosis in human lung carcinoma cells in vitro and in vivo. This study focused on the effect of elevated pressure on the sensitization of TRAIL-resistant cells and the underlying mechanism. We observed elevated pressure-induced sensitization to TRAIL-mediated apoptosis in Hep3B cells, accompanied by the activation of several caspases and the mitochondrial signaling pathway. Interestingly, the enhanced apoptosis induced by elevated pressure was correlated with suppression of extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) phosphorylation and CREB without any change to other MAPKs. Phosphorylation of Bcl-2-associated death promoter (BAD) also decreased, leading to inhibition of the mitochondrial pathway. To confirm whether the activation of pERK1/2 plays a key role in the TRAIL-sensitizing effect of elevated pressure, Hep3B cells were pre-treated with the ERK1/2-specific inhibitor PD98059 instead of elevated pressure. Co-treatment with PD98059 and TRAIL augmented TRAIL-induced apoptosis and decreased BAD phosphorylation. The inhibition of ERK1/2 activation by elevated pressure and PD98059 also reduced BH3 interacting-domain death agonist (BID), thereby amplifying apoptotic stress at the mitochondrial level. Our results suggest that elevated pressure enhances TRAIL-induced apoptosis of Hep3B cells via specific suppression of ERK1/2 activation among MAPKs.

show abstract

“…The NEDD8-activating enzyme inhibitor, MLN4924, was recently shown to cooperate with TRAIL to augment apoptosis through facilitating c-FLIP degradation in head and neck cancer cells [100]. Furthermore, treatment with troglitazone sensitized glioma cells to TRAIL-induced apoptosis regulated by proteasome-dependent degradation of FLIP and ERK1/2-dependent phosphorylation of BAD [101]. Unlike bortezomib, that renders tumor cells resistant to killing by tumor-specific T cells due to impaired antigen processing and presentation, we found that b-AP15 treatment sensitized tumor cells to TRAIL-mediated killing by tumor-specific T cells [102].…”

Section: Modulation Of Tumor Necrosis Factor (Tnf)-related Apoptosmentioning

confidence: 99%

Regulation of TRAIL-Receptor Expression by the Ubiquitin-Proteasome System

Sarhan

D’Arcy

Lundqvist

2014

IJMS

View full text Add to dashboard Cite

The tumor necrosis factor (TNF)-related apoptosis-inducing ligand- receptor (TRAIL-R) family has emerged as a key mediator of cell fate and survival. Ligation of TRAIL ligand to TRAIL-R1 or TRAIL-R2 initiates the extrinsic apoptotic pathway characterized by the recruitment of death domains, assembly of the death-inducing signaling complex (DISC), caspase activation and ultimately apoptosis. Conversely the decoy receptors TRAIL-R3 and TRAIL-R4, which lack the pro-apoptotic death domain, function to dampen the apoptotic response by competing for TRAIL ligand. The tissue restricted expression of the decoy receptors on normal but not cancer cells provides a therapeutic rational for the development of selective TRAIL-mediated anti-tumor therapies. Recent clinical trials using agonistic antibodies against the apoptosis-inducing TRAIL receptors or recombinant TRAIL have been promising; however the number of patients in complete remission remains stubbornly low. The mechanisms of TRAIL resistance are relatively unexplored but may in part be due to TRAIL-R down-regulation or shedding of TRAIL-R by tumor cells. Therefore a better understanding of the mechanisms underlying TRAIL resistance is required. The ubiquitin-proteasome system (UPS) has been shown to regulate TRAIL-R members suggesting that pharmacological inhibition of the UPS may be a novel strategy to augment TRAIL-based therapies and increase efficacies. We recently identified b-AP15 as an inhibitor of proteasome deubiquitinase (DUB) activity. Interestingly, exposure of tumor cell lines to b-AP15 resulted in increased TRAIL-R2 expression and enhanced sensitivity to TRAIL-mediated apoptosis and cell death in vitro and in vivo. In conclusion, targeting the UPS may represent a novel strategy to increase the cell surface expression of pro-apoptotic TRAIL-R on cancer cells and should be considered in clinical trials targeting TRAIL-receptors in cancer patients.

show abstract

Troglitazone-mediated sensitization to TRAIL-induced apoptosis is regulated by proteasome-dependent degradation of FLIP and ERK1/2-dependent phosphorylation of BAD

Cited by 15 publications

References 47 publications

Methylseleninic acid potentiates multiple types of cancer cells to ABT-737-induced apoptosis by targeting Mcl-1 and Bad

Methylseleninic acid potentiates multiple types of cancer cells to ABT-737-induced apoptosis by targeting Mcl-1 and Bad

Elevated pressure enhanced TRAIL-induced apoptosis in hepatocellular carcinoma cells via ERK1/2-inactivation

Regulation of TRAIL-Receptor Expression by the Ubiquitin-Proteasome System

Contact Info

Product

Resources

About