Upregulation of DR5 by proteasome inhibitors potently sensitizes glioma cells to TRAIL‐induced apoptosis
TLDR
Novel therapeutic approaches using TRAIL or agonistic TRAIL receptor antibodies in combination with proteasome inhibitors may represent a promising approach to reactivate apoptosis in therapy‐resistant high‐grade gliomas.Abstract:
This study was undertaken to explore the potential of new therapeutic approaches designed to reactivate cell death pathways in apoptosis-refractory gliomas and to characterize the underlying molecular mechanisms of this reactivation. Here we investigated the sensitivity of a panel of glioma cell lines (U87, U251, U343, U373, MZ-54, and MZ-18) to apoptosis induced by the death receptor ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), TRAIL in combination with gamma irradiation, and TRAIL in combination with proteasome inhibitors (MG132 and epoxomicin). Analysis of these six glioma cell lines revealed drastic differences in their sensitivity to these treatments, with two of the six cell lines revealing no significant induction of cell death in response to TRAIL alone. Interestingly, the proteasome inhibitors MG132 and epoxomicin were capable of potentiating TRAIL-induced apoptosis in TRAIL-sensitive U87 and U251 cells and of reactivating apoptosis in TRAIL-resistant U343 and U373 cells. In contrast, gamma irradiation had no synergistic effects with TRAIL in the two TRAIL-resistant cell lines. RNA interference against death receptor 5 (DR5) revealed that reactivation of TRAIL-induced apoptosis by proteasome inhibitors depended on enhanced transcription and surface expression of DR5. Transient knockdown of the transcription factor GADD153/C/EBP homologous protein and application of the synthetic c-Jun N-terminal kinase inhibitor SP600125 indicated that enhanced DR5 expression occurred independently of GADD153/C/EBP homologous protein, but required activation of the c-Jun N-terminal kinase/c-Jun signaling pathway. Novel therapeutic approaches using TRAIL or agonistic TRAIL receptor antibodies in combination with proteasome inhibitors may represent a promising approach to reactivate apoptosis in therapy-resistant high-grade gliomas.read more
Citations
More filters
Journal ArticleDOI
Cancer drug resistance: an evolving paradigm
TL;DR: There are now unprecedented opportunities to understand and overcome drug resistance through the clinical assessment of rational therapeutic drug combinations and the use of predictive biomarkers to enable patient stratification.
Journal ArticleDOI
New frontiers in promoting tumour cell death: targeting apoptosis, necroptosis and autophagy
J S Long,Kevin M. Ryan +1 more
TL;DR: This review provides an insightful overview of the common forms of cell death signalling pathways, the interactions between these pathways and the ways in which these pathways are deregulated in cancer.
Journal ArticleDOI
Subcellular targets of cisplatin cytotoxicity: An integrated view
Sandra M. Sancho-Martínez,Laura Prieto-García,Marta Prieto,José M. López-Novoa,Francisco J. López-Hernández +4 more
TL;DR: This article critically summarizes the available information in order to establish the connection among its known subcellular effects in a hierarchical and integrative framework and considers the potential utility of this information in the improvement of the pharmacotoxicological profile of this drug.
Journal ArticleDOI
Cancer-type-specific crosstalk between autophagy, necroptosis and apoptosis as a pharmacological target.
TL;DR: The effects of pharmacologically active compounds as modulators of different types of cancer cell death depending on the cellular context are summarized to highlight the potential role of these compounds for context-specific anticancer therapy.
Journal ArticleDOI
TRAILing death in cancer.
TL;DR: An overview of the biology, function and translational relevance of TRAIL is presented with a specific view to discussing the various regulatory mechanisms and the current trends in reverting TRAIL resistance of cancer cells with the obvious implication of an improved clinical outcome.
References
More filters
Journal ArticleDOI
Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity.
Michael Karin,Yinon Ben-Neriah +1 more
TL;DR: Recent progress has been made in understanding the details of the signaling pathways that regulate NF-kappaB activity, particularly those responding to the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-1.
Journal ArticleDOI
Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules
Kenneth L. Rock,Colette F. Gramm,Lisa Rothstein,Karen Clark,Ross L. Stein,Lawrence Dick,Daniel Hwang,Alfred L. Goldberg +7 more
TL;DR: Peptide aldehydes that inhibit major peptidase activities of the 20S and 26S proteasomes are shown to reduce the degradation of protein and ubiquitinated protein substrates by 26S particles.
Journal ArticleDOI
The WHO Classification of Tumors of the Nervous System
Paul Kleihues,David N. Louis,Bernd W. Scheithauer,Lucy B. Rorke,Guido Reifenberger,Peter C. Burger,Webster K. Cavenee +6 more
TL;DR: The new World Health Organization (WHO) classification of nervous system tumors, published in 2000, emerged from a 1999 international consensus conference of neuropathologists, and new entities include chordoid glioma of the third ventricle, cerebellar liponeurocytoma, atypical teratoid/rhabdoid tumor, and perineurioma.
Journal ArticleDOI
Malignant glioma: Genetics and biology of a grave matter
Elizabeth A. Maher,Frank B. Furnari,Robert M. Bachoo,David H. Rowitch,David N. Louis,Webster K. Cavenee,Ronald A. DePinho +6 more
TL;DR: Although a comprehensive view of the genetic lesions encountered in malignant gliomas has been compiled, substantive conceptual and practical barriers remain in assigning functional significance to these genetic changes and in harnessing this basic information into the development of drugs that make a difference in patient care.
Journal ArticleDOI
The proteasome: a suitable antineoplastic target
TL;DR: A proteasome inhibitor — bortezomib — has been developed that has shown efficacy as an anticancer agent in the clinic and how can targeting such a universal, broadly active cellular component provide the selectivity and specificity that are required for cancer therapeutics?
Related Papers (5)
Safety and antitumor activity of recombinant soluble Apo2 ligand
CHOP Is Involved in Endoplasmic Reticulum Stress-induced Apoptosis by Enhancing DR5 Expression in Human Carcinoma Cells
Wild-type p53 transactivates the KILLER/DR5 gene through an intronic sequence-specific DNA-binding site
Rishu Takimoto,Wafik S. El-Deiry +1 more