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KMID : 1134120090120030134
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Journal of Breast Cancer
2009 Volume.12 No. 3 p.134 ~ p.141
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Reactive Oxygen Species Generated by 17β-estradiol Play a Role in the Up-regulation of GPX4 Protein in MCF-7 Breast Cancer Cells
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Lee Sang-Han
Kim Hee-Jeong
Kang Hyo-Jin
Lee Yoon-Jin
Nam Hae-Seon
Bae In-Soo
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Abstract
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Purpose: Estrogen is known to act as both a growth factor and a survival factor for breast cancer. The responsible molecular mechanisms remain, however, to be fully elucidated. We hypothesize that the effect of estrogen relates to its ability to induce the cellular antioxidant defense enzymes.
Methods: In the presence study, we examined the ability of 17β-estradiol (E2) to regulate the level of phospholipid hydroperoxide glutathione peroxidase (GPX4) protein, which is an anti-oxidative enzyme that can directly reduce both phospholipids and cholesterol-hydroperoxides located in the cell membranes and lipoproteins.
Results: E2 elicited a dose- and time-dependent increase in the GPX4 expression in the MCF-7 breast cancer cells, and this up-regulation was blocked by the free radical scavenger N-acetylcysteine (NAC). Additionally, we confirmed that E2 triggered a rapid and transient increase in the intracellular reactive oxygen species (ROS) levels, and this E2-induced increase in the ROS levels was inhibited by pretreatment with NAC. Moreover, such ROS inducers as TGF-β, TNF-αand insulin induced an increase in the level of GPX4 protein. However, estrogen receptor (ER)αknockdown by transfection with ERα-siRNA did not significantly change the GPX4 protein level that was induced by E2. Furthermore, pre-incubation with the ER antagonist ICI 182,780 did not inhibit E2-mediated GPX4 induction. Conversely, pretreatment of cells with LY294002, a pharmacological inhibitor of phosphatidylinositol 3-kinase inhibitor, suppressed the E2- augmented GPX4 expression.
Conclusion: Collectively, our data show that E2 may partly provide a survival advantage through the regulation of cellular oxidative homeostasis in MCF- 7 breast cancer cells.
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KEYWORD
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17β-estradiol, Estrogen receptors, Glutathione peroxidase, Oxidative stress, Reactive oxygen species
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