A NADPH oxidase-dependent redox signaling pathway mediates the selective radiosensitization effect of parthenolide in prostate cancer cells.
A NADPH oxidase-dependent redox signaling pathway mediates the selective radiosensitization effect of parthenolide in prostate cancer cells.
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DOI：
10.1158/0008-5472.can-09-4572
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发表时间：
2010-04-01
期刊：
影响因子：
11.2
通讯作者：
St Clair WH
中科院分区：
文献类型：
--
作者：
Sun Y;St Clair DK;Xu Y;Crooks PA;St Clair WH
癌细胞通常比正常细胞承受更高的氧化应激。我们假设引入额外的ROS损伤或抑制抗氧化能力可能会通过应激超载或应激敏化选择性地增强氧化应激产生剂对癌细胞的杀伤，而正常细胞可能能够通过适应性反应在外源ROS下维持氧化还原稳态。在这里，我们证明小白菊内酯（PN）是一种倍半萜内酯，选择性地对前列腺癌 PC3 细胞表现出放射增敏作用，但对正常前列腺上皮 PrEC 细胞没有放射增敏作用。 PN 会在 PC3 细胞中引起氧化应激，但不会在 PrEC 细胞中引起氧化应激，这是通过 ROS 敏感探针 H2DCFDA 的氧化以及细胞内硫醇和二硫化物水平的降低来确定的。在 PC3（而非 PrEC）细胞中，PN 激活 NADPH 氧化酶，导致还原型硫氧还蛋白水平降低、PI3K/Akt 激活以及随后的 FOXO3a 磷酸化，从而导致 FOXO3a 靶标、抗氧化酶锰超氧化物歧化酶 (MnSOD) 和过氧化氢酶的下调。重要的是，当与放射结合时，PN 进一步增加 PC3 细胞中的 ROS 水平，同时可能通过增加 GSH 水平来减少 PrEC 细胞中放射诱导的氧化应激。总之，结果表明，PN 选择性激活 NADPH 氧化酶，并通过增加 ROS 生成和降低抗氧化防御能力来介导前列腺癌细胞中的强烈氧化应激。这些结果支持了利用癌细胞和正常细胞氧化还原状态的内在差异作为选择性杀死癌症的目标的概念。
Cancer cells are usually under higher oxidative stress than normal cells are. We hypothesize that introducing additional ROS insults or suppressing antioxidant capacity may selectively enhance cancer cell killing by oxidative-stress generating agents through stress overload or stress sensitization, while normal cells may be able to maintain redox homeostasis under exogenous ROS by adaptive response. Here, we demonstrate that parthenolide (PN), a sesquiterpene lactone, selectively exhibits a radiosensitization effect on prostate cancer PC3 cells but not on normal prostate epithelial PrEC cells. PN causes oxidative stress in PC3 cells but not in PrEC cells, as determined by the oxidation of the ROS-sensitive probe H2DCFDA and intracellular reduced thiol and disulfide levels. In PC3 but not PrEC cells, PN activates NADPH oxidase leading to a decrease in the level of reduced thioredoxin, activation of PI3K/Akt and consequent FOXO3a phosphorylation, which results in the downregulation of FOXO3a targets, antioxidant enzyme manganese superoxide dismutase (MnSOD) and catalase. Importantly, when combined with radiation, PN further increases ROS levels in PC3 cells, while it decreases radiation-induced oxidative stress in PrEC cells, possibly by increasing GSH level. Together, the results demonstrate that PN selectively activates NADPH oxidase and mediates intense oxidative stress in prostate cancer cells by both increasing ROS generation and decreasing antioxidant defense capacity. The results support the concept of exploiting the intrinsic differences in the redox status of cancer cells and normal cells as targets for selective cancer killing.