Journal
CELL DEATH AND DIFFERENTIATION
Volume 17, Issue 8, Pages 1288-1301Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2010.9
Keywords
TRAIL; TAK1; p38 MAPK; MCL-1; MOMP
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Funding
- American Cancer Society [RSG-05-029-01-CCG]
- NCI/NIH [CA129521]
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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. Cell Death and Differentiation (2010) 17, 1288-1301; doi:10.1038/cdd.2010.9; published online 19 February 2010
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