Molecular cross-talk between the TRAIL and interferon signaling pathways.
TRAIL/APO-2L induces apoptosis in a variety of transformed cells and has potential as an anti-cancer therapeutic. The physiologic role of TRAIL is presumably more complex than merely activating caspase-mediated cell death. To shed light into TRAIL-mediated signaling, we used DNA microarrays to profile gene expression mediated by TRAIL in breast carcinoma cells. Primary response genes induced by TRAIL included a number of known NF-kappaB-dependent genes such as cIAP2, A20, and E-selectin. Remarkably, global transcriptome analysis revealed that TRAIL also induced a cohort of genes related to the interferon-signaling pathway. Assessing interferon-induced gene expression suggested various points of interaction with the TRAIL signaling pathway. Interestingly, while we observed interferon-mediated up-regulation of TRAIL, we also demonstrated a concomitant TRAIL-mediated induction of interferon-beta. Combining TRAIL and interferon in vitro, synergistically induced apoptosis and caspase activation in breast cancer cells. Together, these data indicate multiple levels of molecular cross-talk between the two diverse cytokines with anti-tumor properties.
Kumar-Sinha
Chandan
C
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Varambally
Sooryanarayana
S
Sreekumar
Arun
A
Chinnaiyan
Arul M
AM
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D007372:Interferons / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D005810:Multigene Family; D020411:Oligonucleotide Array Sequence Analysis; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation
D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D007372:Interferons; D003513:Cycloheximide; D020169:Caspases