Inhibition of pyruvate carboxylase by 1α,25-dihydroxyvitamin D promotes oxidative stress in early breast cancer progression.
Inhibition of pyruvate carboxylase by 1α,25-dihydroxyvitamin D promotes oxidative stress in early breast cancer progression.
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DOI：
10.1016/j.canlet.2017.09.045
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发表时间：
2017-12-28
期刊：
影响因子：
9.7
通讯作者：
Teegarden D
中科院分区：
文献类型：
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作者：
Wilmanski T;Zhou X;Zheng W;Shinde A;Donkin SS;Wendt M;Burgess JR;Teegarden D
维持还原-氧化（氧化还原）平衡是乳腺癌细胞存活的一个基本特征，细胞代谢通过供应还原型NADPH在维持氧化还原平衡中发挥着不可或缺的作用。在本研究中，研究了1，25-二羟维生素D（1，25（OH）2D）对乳腺癌早期氧化还原平衡的影响。用1，25（OH）2D处理促进了MCF 10A-ras和MCF 10A-ErbB 2乳腺上皮细胞中的氧化应激，如通过降低NADPH/NADP+和还原为氧化型谷胱甘肽（GSH/GSSG）的比率所测量的。丙酮酸羧化酶（PC）的mRNA和蛋白质表达下调与1，25（OH）2D处理，这表明一个潜在的机制。MCF 10A-ras细胞中PC基因的缺失导致NADPH/NADP+和GSH/GSSG比值的降低，而1，25（OH）2D处理没有进一步的影响。突变分析证实了PC基因启动子区域中维生素D反应元件的存在和功能。总的来说，这些结果提供了证据表明，1，25（OH）2D通过PC的转录下调促进早期乳腺癌进展中的氧化应激。
Maintaining reductive-oxidative (redox) balance is an essential feature in breast cancer cell survival, with cellular metabolism playing an integral role in maintaining redox balance through its supply of reduced NADPH. In the present studies, the effect of 1,25-dihydroxyvitamin D (1,25(OH)2D) on redox balance was investigated in early stages of breast cancer. Treatment with 1,25(OH)2D promoted oxidative stress in MCF10A-ras and MCF10A-ErbB2 breast epithelial cells, as measured by the decreased ratios of NADPH/NADP+ and reduced to oxidized glutathione (GSH/GSSG). The mRNA and protein expression of the enzyme pyruvate carboxylase (PC) was downregulated with 1,25(OH)2D treatment, suggesting a potential mechanism. Genetic depletion of PC in MCF10A-ras cells resulted in a decreased ratio of NADPH/NADP+ and GSH/GSSG, with 1,25(OH)2D treatment having no further effect. Mutation analysis confirmed the presence and functionality of a vitamin D response element in the PC gene promoter region. Collectively, these results provide evidence that 1,25(OH)2D promotes oxidative stress in early breast cancer progression through transcriptional downregulation of PC.
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