KMID : 1140220200250020100
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´ëÇѾϿ¹¹æÇÐȸÁö 2020 Volume.25 No. 2 p.100 ~ p.110
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15-Deoxy-¥Ä12,14-prostaglandin J2 Induces Apoptosis in Ha-ras-transformed Human Breast Epithelial Cells by Targeting I¥êB kinase?NF-¥êB Signaling
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Na Hye-Kyung
Yang Hong-Kyung Surh Young-Joon
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Abstract
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15-Deoxy-¥Ä12,14-prostaglandin J2 (15d-PGJ2), an endogenous ligand for PPAR¥ã, has differential effects on cancer cell proliferation and survival depending on the dose and the type of cells. In the present study, we have investigated the effects of 15d-PGJ2 on apoptosis of the Ha-ras transformed human breast epithelial (MCF10A-ras) cells. When MCF10A-ras cells were treated with 15d-PGJ2 (10 ¥ìM) for 24 hours, they underwent apoptosis as evidenced by characteristic morphological features, an increased proportion of sub-G0/G1 cell population, a typical pattern of annexin V/propidium iodide staining, perturbation of mitochondrial transmembrane potential (¥Ä¥÷m), and cleavage of caspase-3 and its substrate PARP. A pan-caspase inhibitor, Z-Val-Ala-Asp (OCH3)-fluoromethyl ketone attenuated cytotoxicity and proteolytic cleavage of caspase-3 induced by 15d-PGJ2. The 15d-PGJ2-induced apoptosis was accompanied by enhanced intracellular accumulation of reactive oxygen species (ROS), which was abolished by the antioxidant N-acetyl-L-cysteine (NAC). 15d-PGJ2 inhibited the DNA binding activity of NF-¥êB which was associated with inhibition of expression and catalytic activity of I¥êB kinase ¥â (IKK¥â). 15d-PGJ2-mediated inhibition of IKK¥â and nuclear translocation of phospho- p65 was blocked by NAC treatment. 9,10-Dihydro-PGJ2, a non-electrophilic analogue of 15d-PGJ2, failed to produce ROS, to inhibit NF-¥êB DNA binding, and to induce apoptosis, suggesting that the electrophilic ¥á,b-unsaturated carbonyl group of 15d-PGJ2 is essential for its pro-apoptotic activity. 15d-PGJ2-induced inactivation of IKK¥â was also attributable to its covalent thiol modification at the cysteine 179 residue of IKK¥â. Based on these findings, we propose that 15d-PGJ2 inactivates IKK¥â?¥ÍF-¥êB signaling through oxidative or covalent modification of IKK¥â, thereby inducing apoptosis in Ha-ras transformed human breast epithelial cells.
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KEYWORD
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15-Deoxy-¥Ä12,14-prostaglandin J2, Apoptosis, Reactive oxygen species, IKK¥â?NF-kB, MCF10A-ras cells
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