Low concentrations of diindolylmethane, a metabolite of indole-3-carbinol, protect against oxidative stress in a BRCA1-dependent manner.
Low concentrations of diindolylmethane, a metabolite of indole-3-carbinol, protect against oxidative stress in a BRCA1-dependent manner.
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DOI：
10.1158/0008-5472.can-08-3309
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发表时间：
2009-08-01
期刊：
影响因子：
11.2
通讯作者：
Rosen EM
中科院分区：
文献类型：
--
作者：
Fan S;Meng Q;Saha T;Sarkar FH;Rosen EM
吲哚-3-甲醇（I3 C）代谢产物3，3-二吲哚基甲烷（DIM）是一种用于各种肿瘤类型（包括乳腺癌）的建议癌症预防剂。在这里，我们表明，DIM上调肿瘤抑制蛋白BRCA 1在癌细胞和正常细胞类型的表达。BRCA 1的上调是剂量和时间依赖性的;当细胞暴露72小时时，在生理相关的微摩尔和亚微摩尔DIM浓度下观察到。用母体化合物（I3 C）或DIM（1 µM）处理可防止H2 O2和其他氧化剂导致的细胞杀伤; BRCA 1的敲除可消除这种保护作用。DIM通过抗氧化剂应答元件以BRCA 1依赖性方式刺激抗氧化剂转录因子NFE 2L 2（NRF 2）的信号传导。我们进一步表明，DIM迅速刺激BRCA 1在丝氨酸-1387和丝氨酸-1524上的磷酸化，并且这些磷酸化是保护免受氧化应激所必需的。DIM诱导的BRCA 1丝氨酸-1387磷酸化依赖于ATM。最后，在我们的检测系统中，H2 O2诱导的细胞死亡不是由于细胞凋亡。然而，细胞死亡的一个重要组成部分可归因于自噬; DIM和BRCA 1都抑制H2 O2诱导的自噬。我们的研究结果表明，低浓度的DIM通过几种不同的机制通过肿瘤抑制因子BRCA 1保护细胞免受氧化应激。
The indole-3-carbinol (I3C) metabolite 3,3-diindolylmethane (DIM) is a proposed cancer prevention agent for various tumor types, including breast cancer. Here, we show that DIM up-regulates expression of the tumor suppressor protein BRCA1 in carcinoma and normal cell types. Up-regulation of BRCA1 was dose- and time-dependent; and it was observed at physiologically relevant micromolar and submicromolar DIM concentrations when cells were exposed for 72 hr. Treatment with the parent compound (I3C) or DIM (1 µM) protected against cell killing due to H2O2 and other oxidants; and the protection was abrogated by knockdown of BRCA1. DIM stimulated signaling by the antioxidant transcription factor NFE2L2 (NRF2) through the antioxidant response element in a BRCA1-dependent manner. We further showed that DIM rapidly stimulated phosphorylation of BRCA1 on serine-1387 and serine-1524 and that these phosphorylations are required for protection against oxidative stress. DIM-induced phosphorylation of BRCA1 on serine-1387 was dependent upon ATM. Finally, in our assay systems, H2O2-induced cell death was not due to apoptosis. However, a significant component of cell death was attributable to autophagy; and both DIM and BRCA1 inhibited H2O2-induced autophagy. Our findings suggest that low concentrations of DIM protect cells against oxidative stress via the tumor suppressor BRCA1 by several distinct mechanisms.