Selective Inhibition of IκB Kinase Sensitizes Mantle Cell Lymphoma B Cells to TRAIL by Decreasing Cellular FLIP Level

Abstract

In an attempt to circumvent the intrinsic resistance of mantle cell lymphoma (MCL) cells to apoptosis, we have analyzed their sensitivity to the extrinsic apoptotic signal triggered by TRAIL. We show here that TRAIL can trigger apoptosis in a majority of MCL cell lines and primary cultures, irrespective of receptor levels, Bcl-2 family members, or caspase regulator expression. MCL sensitivity to TRAIL was closely linked to the activity of the NF-κB p50 factor and to the consequent expression of cellular FLIP (c-FLIP), which accumulated into the TRAIL-dependent complex in resistant cells. c-FLIP transient knockdown overcame MCL resistance to TRAIL, while NF-κB inhibitors differentially modulated TRAIL cytotoxicity. Indeed, bortezomib increased TRAIL cytotoxic effects in sensitive cells, but led to the intracellular accumulation of c-FLIP, impeding full synergistic interaction. In contrast, the IκB kinase inhibitor BMS-345541 led to decreased c-FLIP expression and allowed all MCL samples to undergo TRAIL-mediated apoptosis. These results present the combination of TRAIL stimulation and IκB kinase inhibition as a new approach to MCL therapy.

The EMT activator ZEB1 promotes tumor growth and determines differential response to chemotherapy in mantle cell lymphoma

“…1 In this regard, several classical transduction pathways involved in cancer (for example, NF-kB, Notch, PI3K/AKT/mTOR, and Wnt) are constitutively active in different subsets of MCLs. 1,[3][4][5][6] Here, we show that ZEB1, a transcription factor that has a key role in EMT and carcinoma progression, is found in the same subset of primary MCLs that express bcatenin. ZEB1 expression in MCL cells is dependent on Wnt as further activation of Wnt signaling upregulates ZEB1, whereas interference of the pathway -either by knockdown of b-catenin or treatment with Wnt inhibitor salinomycin -downregulates it.…”

“…In that regard, chromosomal alterations and nongenetic modifications resulting in the constitutive activation of pro-oncogenic signals (for example, NF-kB, Notch, PI3K/AKT/mTOR, and Wnt) and/or deregulation of DNA repair and apoptotic pathways and genes (for example, AKT, BCL2, MCL1) have been found in subsets of MCLs, providing additional levels of plasticity in the genesis and progression of the disease. 1,[3][4][5][6][7][8][9][10][11] Of particular interest is the canonical Wnt pathway that has a crucial role in normal hematopoiesis and whose aberrant activation, long known to drive tumorigenesis in solid tumors, has also been involved in a number of hematological malignancies, including MCLs. 3,5,6,[12][13][14][15][16][17][18][19]20 In addition to gain-of-function mutations of intracellular components of the Wnt pathway, overexpression of Wnt receptors and ligands or downregulation of Wnt inhibitors through nongenetic modifications are also common.…”

Withaferin A sensitizes TRAIL-induced apoptosis through reactive oxygen species-mediated up-regulation of death receptor 5 and down-regulation of c-FLIP

“…Recently, down-regulation of c-FLIP has been proposed to contribute to the sensitization of TRAIL-induced apoptosis by MG-132 or IκB kinase inhibitor [21,22]. We found that two isoforms of c-FLIP, c-FLIP L and c-FLIP S , were markedly decreased in a dosedependent manner in various cancer cells, including Caki, Hep3B, SK-Hep1, and Huh7 cells, treated with Wit A (Fig.…”

PRMT5, a Novel TRAIL Receptor-Binding Protein, Inhibits TRAIL-Induced Apoptosis via Nuclear Factor-κB Activation

“…We used the IKK inhibitor BMS-345541 (33,34). As expected, NF-κB inhibition by BMS-345541 potentiated cell death induced by TRAIL as well as by TNF-α in HCT116, HT1080/ DR4 (Fig.…”