TY - JOUR
T1 - TRAIL-activated stress kinases suppress apoptosis through transcriptional upregulation of MCL-1
AU - Son, J. K.
AU - Varadarajan, S.
AU - Bratton, S. B.
N1 - Funding Information:
Acknowledgements. We wish to thank Dr. X-M Sun and Professor GM Cohen for generously providing caspase-8 and Smac/DIABLO antibodies. We are also grateful to Dr. Kevin N Dalby, Dr. Colin S Duckett, Professor David Engelberg, Dr. Xin Lin, Dr. Jiahuai Han, Dr. Dean G Tang, and Dr. Casey W Wright for providing plasmids and cell lines. This work was supported in part by grants from The American Cancer Society RSG-05-029-01-CCG and the NCI/NIH CA129521 (to SBB).
PY - 2010/8
Y1 - 2010/8
N2 - 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-Β-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, SmacDIABLO, 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.
AB - 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-Β-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, SmacDIABLO, 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.
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U2 - 10.1038/cdd.2010.9
DO - 10.1038/cdd.2010.9
M3 - Article
C2 - 20168333
AN - SCOPUS:77954659814
SN - 1350-9047
VL - 17
SP - 1288
EP - 1301
JO - Cell death and differentiation
JF - Cell death and differentiation
IS - 8
ER -