Abstract
Mouse fibroblast cells overexpressing phosphatidylinositol transfer protein alpha [PI-TPalpha; sense PI-TPalpha (SPIalpha) cells] show a significantly increased rate of proliferation and an extreme resistance toward ultraviolet- or tumor necrosis factor-alpha-induced apoptosis. The conditioned medium (CM) from SPIalpha cells or the neutral lipid extract from CM stimulated the proliferation of quiescent wild-type NIH3T3 cells. CM was also highly effective in increasing resistance toward induced apoptosis in both wild-type cells and the highly apoptosis-sensitive SPIbeta cells (i.e., wild-type cells overexpressing PI-TPbeta). CM from SPIalpha cells grown in the presence of NS398, a specific cyclooxygenase-2 (COX-2) inhibitor, expressed a diminished mitogenic and antiapoptotic activity. This strongly suggests that at least one of the bioactive factor(s) is an eicosanoid. In accordance, SPIalpha cells express enhanced levels of COX-1 and COX-2. The antiapoptotic activity of CM from SPIalpha cells tested on SPIbeta cells was inhibited by approximately 50% by pertussis toxin and suramin as well as by SR141716A, a specific antagonist of the cannabinoid 1 receptor. These inhibitors had virtually no effect on the COX-2-independent antiapoptotic activity of CM from SPIalpha cells. The latter results imply that PI-TPalpha mediates the production of a COX-2-dependent eicosanoid that activates a G-protein-coupled receptor, most probably a cannabinoid 1-like receptor.
Highlights
Mouse fibroblast cells overexpressing phosphatidylinositol transfer protein ␣ [Phosphatidylinositol transfer proteins (PI-TPs)␣; sense PI-TP␣ (SPI␣) cells] show a significantly increased rate of proliferation and an extreme resistance toward ultraviolet- or tumor necrosis factor-␣-induced apoptosis
In view of this highly increased rate of proliferation, conditioned medium (CM) from SPI␣ cells were tested for the production of a mitogenic factor by measuring the incorporation of [3H]thymidine into DNA of serum-starved (24–48 h) wtNIH3T3 cells
We show that NIH3T3 cells overexpressing PI-TP␣ (SPI␣ cells) are almost completely resistant toward UV-induced apoptosis compared with wtNIH3T3 cells
Summary
Mouse fibroblast cells overexpressing phosphatidylinositol transfer protein ␣ [PI-TP␣; sense PI-TP␣ (SPI␣) cells] show a significantly increased rate of proliferation and an extreme resistance toward ultraviolet- or tumor necrosis factor-␣-induced apoptosis. CM from SPI␣ cells grown in the presence of NS398, a specific cyclooxygenase-2 (COX-2) inhibitor, expressed a diminished mitogenic and antiapoptotic activity This strongly suggests that at least one of the bioactive factor(s) is an eicosanoid. These inhibitors had virtually no effect on the COX-2-independent antiapoptotic activity of CM from SPI␣ cells The latter results imply that PI-TP␣ mediates the production of a COX-2-dependent eicosanoid that activates a G-protein-coupled receptor, most probably a cannabinoid 1-like receptor.—Schenning, M., C. We present evidence that this regulation occurs through the COX-2-dependent production and secretion of eicosanoid factor(s) One of these factors most likely acts on the G-protein-coupled cannabinoid 1 receptor, thereby displaying both autocrine and paracrine activity
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