Attenuation of Antioxidant Capacity in Human Breast Cancer Cells by Carbon Monoxide through Inhibition of Cystathionine β-Synthase Activity: Implications in Chemotherapeutic Drug Sensitivity
Attenuation of Antioxidant Capacity in Human Breast Cancer Cells by Carbon Monoxide through Inhibition of Cystathionine β-Synthase Activity: Implications in Chemotherapeutic Drug Sensitivity
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DOI：
10.1021/acs.jmedchem.7b00476
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发表时间：
2017-10-12
影响因子：
7.3
通讯作者：
Mascharak, Pradip K.
中科院分区：
文献类型：
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作者：
Kawahara, Brian;Moller, Travis;Mascharak, Pradip K.
耐药性是有效治疗乳腺癌的主要障碍。与正常细胞相比，癌细胞由于还原型谷胱甘肽与氧化型谷胱甘肽 (GSH/GSSG) 的比例增加，因此具有更高的抗氧化潜力。已知这会产生治疗耐药性。在这里，我们发现了乳腺癌细胞特有的一种机制，即胱硫醚β-合酶（CBS）可促进 GSH/GSSG 升高。人乳腺癌细胞中 CBS 的慢病毒沉默减弱了 GSH/GSSG、总 GSH、核因子红细胞 2 相关因子 2 (Nrf2) 以及 Nrf2 下游促进 GSH 合成和从 GSSG 再生 GSH 的过程。一氧化碳 (CO) 通过抑制 CBS 来减少三种乳腺癌细胞系中的 GSH/GSSG。此外，CO 使乳腺癌细胞对阿霉素敏感。这些结果提供了对 CBS 增加抗氧化潜力以及 CO 抑制 CBS 活性以改变乳腺癌氧化还原稳态的能力的机制的深入了解，从而增加了对化疗的敏感性。
Drug resistance is a major impediment to effective treatment of breast cancer. Compared to normal cells, cancer cells have an increased antioxidant potential due to an increased ratio of reduced to oxidized glutathione (GSH/GSSG). This is known to confer therapeutic resistance. Here, we have identified a mechanism, unique to breast cancer cells, whereby cystathionine beta-synthase (CBS) promotes elevated GSH/GSSG. Lentiviral silencing of CBS in human breast cancer cells attenuated GSH/GSSG, total GSH, nuclear factor erythroid 2-related factor 2(Nrf2), and processes downstream of Nrf2 that promote GSH synthesis and regeneration of GSH from GSSG. Carbon monoxide (CO) reduced GSH/GSSG in three breast cancer cell lines by inhibiting CBS. Furthermore, CO sensitized breast cancer cells to doxorubicin. These results provide insight into mechanism(s) by which CBS increases the antioxidant potential and the ability for CO to inhibit CBS activity to alter redox homeostasis in breast cancer, increasing sensitivity to a chemotherapeutic.