Suppression of ERK signaling evokes autocrine Fas-mediated death in arachidonic acid-treated human chronic myeloid leukemia K562 cells

Ku-Chung Chen, Wen-Hsin Liu, Long-Sen Chang
Journal of Cellular Physiology 2010, 222 (3): 625-34
Arachidonic acid (AA)-induced apoptotic death of K562 cells (human chronic myeloid leukemic cells) was characteristic of reactive oxygen species (ROS) generation and mitochondrial depolarization. N-Acetylcysteine pretreatment rescued viability of AA-treated cells and abolished mitochondrial depolarization. In contrast to no significant changes in phospho-JNK and phospho-ERK levels, AA evoked notable activation of p38 MAPK. Unlike that of JNK and p38 MAPK, ERK suppression further reduced the viability of AA-treated cells. Increases in Fas/FasL protein expression, caspase-8 activation, the production of tBid and the loss of mitochondrial membrane potential were noted with K562 cells that were treated with a combination of U0126 and AA. Down-regulation of FADD attenuated U0126-evoked degradation of procaspase-8 and Bid. Abolition of p38 MAPK activation abrogated U0126-elicited Fas/FasL up-regulation in AA-treated cells. U0126 pretreatment suppressed c-Fos phosphorylation but increased p38 MAPK-mediated c-Jun phosphorylation. Knock-down of c-Fos and c-Jun protein expression by siRNA suggested that c-Fos counteracted the effect of c-Jun on Fas/FasL up-regulation. Taken together, our data indicate that AA induces the ROS/mitochondria-dependent death pathway and blocks the ERK pathway which enhances the cytotoxicity of AA through additionally evoking an autocrine Fas-mediated apoptotic mechanism in K562 cells.

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