TRAIL-activated stress kinases suppress apoptosis through transcriptional upregulation of MCL-1.

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potentially useful anticancer agent with exquisite selectivity for cancer cells. Unfortunately, many cancers show or acquire resistance to TRAIL. In this study we report that TRAIL activates a TGF-beta-activated kinase 1 --> mitogen-activated protein kinase (MAPK) kinase 3 (MKK3)/MKK6 --> p38 pathway in prostate cancer cells that transcriptionally upregulates expression of the antiapoptotic BCL-2 family member MCL-1. TRAIL alone triggered robust formation of the 'death-inducing signaling complex' (DISC), activation of the initiator caspase-8, and truncation of the BH3-only protein BID (tBID). Nevertheless, simultaneous disruption of the p38 MAPK pathway was required to suppress MCL-1 expression, thereby allowing tBID to activate the proapoptotic BCL-2 family member BAK and stimulate mitochondrial outer membrane permeabilization (MOMP). Release of the inhibitor-of-apoptosis (IAP) antagonist, Smac/DIABLO, from the intermembrane space was sufficient to promote TRAIL-induced apoptosis, whereas release of cytochrome c and activation of the apoptosome was dispensable. Even after MOMP, however, mitochondrial-generated reactive oxygen species (ROS) activated a secondary signaling pathway, involving c-Jun N-terminal kinases (JNKs), that similarly upregulated MCL-1 expression and partially rescued some cells from death. Thus, stress kinases activated at distinct steps, before and after mitochondrial injury, mediate TRAIL resistance through maintenance of MCL-1 expression.

• Authors: J K Son, S Varadarajan, S B Bratton
• Journal: Cell death and differentiation (Cell Death Differ) Vol. 17 Issue 8 Pg. 1288-301 (Aug 2010) ISSN: 1476-5403 [Electronic] England
• PMID: 20168333 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• BH3 Interacting Domain Death Agonist Protein
• DIABLO protein, human
• Inhibitor of Apoptosis Proteins
• Intracellular Signaling Peptides and Proteins
• Mitochondrial Proteins
• Myeloid Cell Leukemia Sequence 1 Protein
• Proto-Oncogene Proteins c-bcl-2
• Reactive Oxygen Species
• TNF-Related Apoptosis-Inducing Ligand
• p38 Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 3
• Caspase 8

Topics

• Apoptosis
• Apoptosis Regulatory Proteins
• BH3 Interacting Domain Death Agonist Protein (metabolism)
• Caspase 8 (metabolism)
• Cell Line, Tumor
• Humans
• Inhibitor of Apoptosis Proteins (metabolism)
• Intracellular Signaling Peptides and Proteins (metabolism)
• MAP Kinase Kinase 3 (metabolism)
• Mitochondrial Proteins (metabolism)
• Myeloid Cell Leukemia Sequence 1 Protein
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• Reactive Oxygen Species (metabolism)
• Signal Transduction
• TNF-Related Apoptosis-Inducing Ligand (pharmacology)
• Transcription, Genetic
• Up-Regulation
• p38 Mitogen-Activated Protein Kinases (metabolism)