Activation and Suppression of the TRAIL Death-Receptor Pathway in Chemotherapy Sensitive and Resistant Follicular Lymphoma Cells

Abstract

Aberrant expression of the apoptosis inhibitor bcl-2 provides a survival advantage throughout oncogenesis and can facilitate chemotherapeutic resistance in a variety of human cancers. Follicular lymphoma (FL) for example, is characterized by the chromosomal translocation t(14;18), which results in bcl-2 overexpression and initiates lymphomagenesis. Although FL cells possess ample amounts of bcl-2, they respond remarkably well to standard first-round chemotherapy. However, the vast majority of patients relapses and becomes progressively resistant to therapy. We obtained cell lines derived from chemosensitive and chemoresistant FL patients, that are characterized by the chromosomal translocation t(14;18) and expression of bcl-2, to investigate how chemotherapeutic drugs can circumvent bcl-2 anti-apoptotic function and to identify alterations in those pathways that may facilitate resistance to DNA damaging drugs. In chemosensitive FL cells, we found that DNA damaging drugs promote apoptosis through p53-dependent upregulation of the TRAIL-DR5 receptor, resulting in activation of caspase-8 and downstream executioner caspases, thereby evading bcl-2 mediated suppression of apoptosis. Examination of drug resistant FL cell lines revealed that at least two defects in this pathway can contribute to chemotherapeutic resistance: 1. p53 gene mutations that disable the transcriptional response to DNA damaging drugs, including expression of the TRAIL-DR5 receptor, and 2. transcriptional repression of the cell-death executioner enzyme caspase-3.

Caspase-2 Can Function Upstream of Bid Cleavage in the TRAIL Apoptosis Pathway

“…These antibodies bind and activate DR5 but not other tumor necrosis factor receptors including DR4 and the TRAIL decoy receptors DcR1 and DcR2 (20). Consistent with our previous studies using recombinant TRAIL, siCaspase-2 also suppressed DR5-A-mediated reduction in cell viability (Fig.…”

Mutations in the DNA-binding codons of TP53, which are associated with decreased expression of TRAILreceptor-2, predict for poor survival in diffuse large B-cell lymphoma

“…53 In human tumors, Cillessen et al 54 observed that TRAIL receptor-2 levels are lower in TRAIL-resistant DLBCL, but no data on TP53 were provided in their study. Wagner et al 55 have previously shown, in a microarray analysis of chemoresistant follicular lymphoma cell lines with TP53 mutations, that the abnormal p53 protein cannot up-regulate TRAIL receptor-2 after cells encountered stress from either etoposide or doxorubicin treatment in vitro, which does occur in cell lines with WT TP53. Similarly, Rosenwald et al 28 showed that the level of TRAIL receptor-2 is not up-regulated in a lymphoblastoid cell line with a TP53 mutation treated with fludarabine or irradiation, or in a fludarabine-resistant chronic lymphocytic leukemia with p53 overexpression.…”

“…In vitro studies have shown that the use of exogenous TRAIL or antibodies to TRAIL receptor-2 will stimulate the receptor with the regain of normal apoptosis in lymphoma cell lines with TP53 mutations, [54][55][56] including cell lines derived from DL-BCL. 54 This is in contrast to chronic lymphocyte leukemia or mantle cell lymphoma in which TRAIL receptor 1 (DR4) is activated, but TRAIL receptor-2 is not up-regulated.…”

CCAAT/Enhancer Binding Protein Homologous Protein-Dependent Death Receptor 5 Induction and Ubiquitin/Proteasome-Mediated Cellular FLICE-Inhibitory Protein Down-Regulation Contribute to Enhancement of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Induced Apoptosis by Dimethyl-Celecoxib in Human Non–Small-Cell Lung Cancer Cells

“…It has been documented in the literature that activation of the TRAIL apoptotic pathway such as up-regulation of DR5 contributes to the induction of apoptosis by certain anticancer agents, including celecoxib (Huang et al, 2001;LaVallee et al, 2003;Wagner et al, 2003;Liu et al, 2004b;Kabore et al, 2006). The current work does not address whether DR5 up-regulation participated in the induction of apoptosis by DMC only, although we assume that it may contribute to DMC-induced apoptosis because celecoxib induces apoptosis requiring DR5 up-regulation.…”