Abstract
Arachidonic acid (AA) generated by cytosolic phospholipase A2 (cPLA2) has been suggested to function as a second messenger in tumor necrosis factor (TNF)-induced death signaling. Here, we show that cathepsin B-like proteases are required for the TNF-induced AA release in transformed cells. Pharmaceutical inhibitors of cathepsin B blocked TNF-induced AA release in human breast (MCF-7S1) and cervix (ME-180as) carcinoma as well as murine fibrosarcoma (WEHI-S) cells. Furthermore, TNF-induced AA release was significantly reduced in cathepsin B-deficient immortalized murine embryonic fibroblasts. Employing cPLA2-deficient MCF-7S1 cells expressing ectopic cPLA2 or cPLA2-deficient immortalized murine embryonic fibroblasts, we showed that cPLA2 is dispensable for TNF-induced AA release and death in these cells. Furthermore, TNF-induced cathepsin B-dependent AA release could be dissociated from the cathepsin B-independent cell death in MCF-7S1 cells, whereas both events required cathepsin B activity in other cell lines tested. These data suggest that cathepsin B inhibitors may prove useful not only in the direct control of cell death but also in limiting the damage-associated inflammation.
Highlights
Phospholipase A2 (PLA2)1 family of esterases plays a significant role in inflammation because PLA2s can cleave arachidonic acid (AA) from the sn-2 position of membrane phospholipids and provide it to cyclo- and lipooxygenases, which catalyze its conversion into prostanoids and leukotrienes, respectively [1, 2]
In addition to its functions in disposal of cellular proteins in lysosomes, enhancement of tumor cell invasion by proteolysis of extracellular matrix [31], onset of acute pancreatitis [32] and execution of tumor necrosis factor (TNF)-induced cell death [22], our new data indicate that cathepsin B is an important regulator of TNF-induced Arachidonic acid (AA) release
We showed that cathepsin B-like activity mediates TNF-induced release of AA in cancer cell lines of different origins
Summary
Phospholipase A2 (PLA2)1 family of esterases plays a significant role in inflammation because PLA2s can cleave arachidonic acid (AA) from the sn-2 position of membrane phospholipids and provide it to cyclo- and lipooxygenases, which catalyze its conversion into prostanoids and leukotrienes, respectively [1, 2]. Except for CA-074-Me-treated MCF-7S1 cells dying as effectively as untreated cells despite the significantly reduced AA release, the ability of all other protease inhibitors to inhibit PLA2-like activity correlated well with their ability to inhibit TNF-induced cell death (Fig. 1, A and B).
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