Circadian Stage-Dependent Inhibition of Human Breast Cancer Metabolism and Growth by the Nocturnal Melatonin Signal: Consequences of Its Disruption by Light at Night in Rats and Women
Circadian Stage-Dependent Inhibition of Human Breast Cancer Metabolism and Growth by the Nocturnal Melatonin Signal: Consequences of Its Disruption by Light at Night in Rats and Women
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DOI：
10.1177/1534735409352320
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发表时间：
2009-12-01
影响因子：
2.9
通讯作者：
Hanifin, John P.
中科院分区：
文献类型：
--
作者：
Blask, David E.;Dauchy, Robert T.;Hanifin, John P.
松果体在夜间的褪黑激素昼夜节律生产提供了一个抑制信号，组织分离的类固醇受体SR+和- MCF-7人乳腺癌异种移植在雌性裸鼠。褪黑激素在体内的抗癌作用的一个关键机制涉及褪黑激素受体介导的抑制亚油酸（LA）的摄取及其代谢为促有丝分裂活性的13-羟基十八碳二烯酸（13-HODE）。在夜间将（SR-）异种移植大鼠暴露于强度增加的多色白色光抑制褪黑激素，同时以剂量依赖性方式增加肿瘤生长速率、DNA含量、[3 H]胸苷掺入DNA、LA摄取、13-HODE形成、cAMP水平和ERK 1/2活化。在SR-人乳腺癌异种移植物中发生类似的作用，所述异种移植物在其暴露于夜间单一明亮强度（2800勒克斯）的多色光之后用来自健康女性受试者的褪黑激素耗尽的血液原位灌注。此外，SR-人乳腺癌异种移植物表现出LA摄取、13-HODE形成和增殖活性的强昼夜节律。将异种移植大鼠暴露于夜间昏暗的灯光下，导致这些节律完全消除，最终导致肿瘤代谢和生长的不受约束的高速率。通过抑瘤褪黑激素信号在昼夜节律时间结构内组织肿瘤代谢和生长有助于在癌症及其宿主之间建立平衡，该平衡被宿主在夜间暴露于光而破坏。这种生物学机制可能部分解释了在夜班工作的女性中患乳腺癌和其他癌症的风险较高，也可能解释了其他在夜间长时间暴露在光线下的女性。
The circadian production of melatonin by the pineal gland during the night provides an inhibitory signal to tissue-isolated steroid receptor SR+ and - MCF-7 human breast cancer xenografts in female nude rats. A pivotal mechanism for melatonin's anticancer effects in vivo involves a melatonin receptor-mediated inhibition of linoleic acid (LA) uptake and its metabolism to mitogenically active 13-hydroxyoctadecadienoic acid (13-HODE). Exposure of (SR-) xenograft-bearing rats to increasing intensities of polychromatic white light at night suppresses melatonin while increasing tumor growth rates, DNA content, [3H]thymidine incorporation into DNA, LA uptake, 13-HODE formation, cAMP levels and ERK 1/2 activation a dose-dependent manner. Similar effects occur in SR- human breast cancer xenografts perfused in situ with melatonin-depleted blood from healthy female subjects after their exposure to a single bright intensity (2800 lux) of polychromatic light at night. Additionally, SR- human breast cancer xenografts exhibit robust circadian rhythms of LA uptake, 13-HODE formation and proliferative activity. Exposure of xenograft-bearing rats to dim light at night results in the complete elimination of these rhythms which culminates in unfettered, high rates of tumor metabolism and growth. The organization of tumor metabolism and growth within circadian time structure by the oncostatic melatonin signal helps create a balance between the cancer and its host that is disrupted by host exposure to light at night. This biological mechanism may partially explain the higher risk of breast and other cancers in women working rotating night shifts and possibly others who also experience prolonged exposure to light at night.