Mutant PIK3CA licenses TRAIL and CD95L to induce non-apoptotic caspase-8-mediated ROCK activation

被引：0
作者：
M Ehrenschwender
D Siegmund
A Wicovsky
M Kracht
O Dittrich-Breiholz
V Spindler
J Waschke
H Kalthoff
A Trauzold
H Wajant
机构：
[1] University Hospital Würzburg,Division of Molecular Internal Medicine, Department of Internal Medicine II
[2] Rudolf-Buchheim-Institute of Pharmacology,Department of Anatomy and Cell Biology
[3] University of Gießen,Division of Molecular Oncology
[4] Institute of Biochemistry,undefined
[5] Medical School Hannover,undefined
[6] University of Würzburg,undefined
[7] Köllikerstrasse 6,undefined
[8] 97070 Würzburg,undefined
[9] Germany,undefined
[10] Institute of Experimental Cancer Research,undefined
[11] Comprehensive Cancer Center North,undefined
[12] UK S-H,undefined
[13] Campus Kiel,undefined
[14] Arnold-Heller-Straße 7,undefined
[15] Kiel,undefined
[16] Germany,undefined
来源：
Cell Death & Differentiation | 2010年 / 17卷
关键词：
amoeboid; caspase-8; CD95; PI3K; ROCK-1; TRAIL;
D O I：
暂无
中图分类号：
学科分类号：
摘要：
Constitutively active PI3K catalytic subunit α (PIK3CA) interfered with apoptosis induction downstream of death receptor-signaling complex formation allowing robust caspase-8 activation without triggering the execution steps of apoptosis. In mutant PIK3CA-expressing cells, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and CD95L stimulated nuclear factor kappaB (NFκB) activation, invasion, and transition to an amoeboid-like morphology. NFκB activation and adoption of amoeboid shape were inhibited by caspase-8 knockdown or FLIP-S expression, but only the cell morphology alterations required caspase-8 activity. Furthermore, we identified caspase-8-mediated, caspase-3-independent cleavage of the protein kinase rho-associated, coiled-coil containing protein kinase 1 as a novel mechanism for acquiring amoeboid shape and enhanced invasiveness in response to TRAIL and CD95L. Taken together, we provide evidence that mutated PIK3CA converts the ‘tumor surveillance’ activity of cancer cell-expressed death receptors and caspase-8 toward tumor promotion.
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页码：1435 / 1447
页数：12
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