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- Title
ROS-mediated p38α MAPK activation and ERK inactivation responsible for upregulation of Fas and FasL and autocrine Fas-mediated cell death in Taiwan cobra phospholipase A<sub>2</sub>-treated U937 cells.
- Authors
WEN-HSIN LIU; YUN-CHING CHENG; LONG-SEN CHANG
- Abstract
The aim of the present study is to explore the signaling pathway associated with Naja naja atra phospholipase A2 (PLA2)-induced apoptotic death of human leukemia U937 cells. Degradation of procaspases, production of tBid, loss of mitochondrial membrane potential, and cytochrome c release were observed in PLA2-treated cells. PLA2 treatment increased Fas and FasL protein expression, and upregulated transcription of Fas and FasL mRNA. Upon exposure to PLA2, ROS generation, p38 MAPK activation, and ERK inactivation were found in U937 cells. Abolition of PLA2-induced ROS generation abrogated p38 MAPK activation and upregulation of Fas and FasL expression, but restored ERK activation and viability of PLA2-treated cells. Block of p38 MAPK by SB202190 abolished PLA2-induced Fas/FasL upregulation and ERK inactivation, but not ROS generation. Activated ERK suppressed p38 MAPK activation and Fas/FasL protein expression. Selective inactivation or overexpression of p38α MAPK proved that upregulation of Fas/FasL and ERK inactivation were related to p38α MAPK activation. Deprivation of catalytic activity with PLA2 blocked completely PLA2-induced Fas/FasL upregulation. Downregulation of FADD abolished PLA2-induced procaspase-8 degradation and rescued viability of PLA2-treated cells. Taken together, our results indicate that Fas/FasL upregulation in PLA2-treated U937 cells is elicited by ROS-mediated p38α MAPK activation and ERK inactivation, and suggest that autocrine Fas/FasL apoptotic mechanism is involved in PLA2-induced cell death. J. Cell. Physiol. 219: 642–651, 2009. © 2009 Wiley-Liss, Inc.
- Subjects
NAJA naja; PHOSPHOLIPASES; LEUKEMIA; CELLS; CYTOCHROME c; THERAPEUTICS
- Publication
Journal of Cellular Physiology, 2009, Vol 219, Issue 3, p642
- ISSN
0021-9541
- Publication type
Article
- DOI
10.1002/jcp.21713