Age-related decline in melatonin and its MT1 receptor are associated with decreased sensitivity to melatonin and enhanced mammary tumor growth.
Age-related decline in melatonin and its MT1 receptor are associated with decreased sensitivity to melatonin and enhanced mammary tumor growth.
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DOI：
10.2174/1874609811306010016
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发表时间：
2013-01
影响因子：
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通讯作者：
S. Hill;Chi Cheng;Lin Yuan;L. Mao;R. Jockers;Bob Dauchy;D. Blask
中科院分区：
文献类型：
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作者：
S. Hill;Chi Cheng;Lin Yuan;L. Mao;R. Jockers;Bob Dauchy;D. Blask
松果体激素褪黑激素（MLT）具有有效的抗乳腺癌活性，其作用在很大程度上通过MT 1受体介导，并随后调节下游信号通路，包括cAMP/PKA、Erk/MAPK、p38和Ca 2 +/钙调蛋白。此外，通过MT 1途径，MLT可以抑制一些促有丝分裂核受体（包括ERα、GR和RORα）的转录活性，同时增强参与分化、抗增殖和凋亡的其他受体（RARα和RXRα）的活性。文献综述支持这样的观点，即MLT通过其MT 1受体可以抑制乳腺癌的所有阶段，包括起始、促进和进展。在生命的第五和第六十年，MLT的产生减少，同时乳腺癌的发病率增加。由于MLT已被证明具有抗癌活性，我们假设松果体中MLT产生的减少与乳腺癌的发病率之间可能存在因果关系，乳腺癌的发病率随着年龄的增长而增加。我们设计了这项研究，以确定是否存在一个真正的负相关关系，在年轻（2个月），成年（12个月）和老年（20个月）雌性布法罗大鼠的组织孤立的乳腺肿瘤的生长和减少MLT和MT 1受体随着年龄的增长，这样的因果关系可以找到。与年轻大鼠相比，在成年和衰老大鼠中（降低75%），在夜间峰值测量的血清MLT水平显著降低29%。在年轻大鼠中，夜间松果体MLT含量超过白天水平的19倍，而老年小鼠增加了7倍。此外，MT 1受体被发现是显着降低，在夜间和清晨在衰老大鼠子宫相比，子宫从年轻和成年大鼠。对由N-亚硝基-N-甲基-脲（NMU）诱导的移植的、组织分离的乳腺肿瘤的生长速率的分析显示，在衰老大鼠中显著增加，但在年轻或成年大鼠中没有。在衰老大鼠中注意到对外源性MLT对肿瘤生长的抑制作用的减弱的反应，使得肿瘤生长仅被抑制了33%，而在衰老大鼠中肿瘤生长仅被抑制了48%和66%。在成年和年轻的大鼠分别。与年轻和成年大鼠相比，肿瘤对外源性MLT的反应减少与衰老大鼠MT 1受体表达减少相关。这些数据表明，观察到的与年龄相关的肿瘤生长增强与老年动物中MLT及其受体水平的大幅降低有关，这降低了肿瘤对外源性MLT抑制的敏感性。
The pineal hormone melatonin (MLT) has potent anti-breast cancer activity, its actions are heavily mediated via the MT1 receptor and subsequent modulation of downstream signaling pathways including cAMP/PKA, Erk/MAPK, p38, and Ca2+/calmodulin. Also, via the MT1 pathway, MLT can repress the transcriptional activity of some mitogenic nuclear receptors including ERα, GR, and RORα, while potentiating the activity of other receptors (RARα and RXRα) involved in differentiation, anti-proliferation, and apoptosis. A review of the literature supports the view that MLT, via its MT1 receptor, can suppress all phases of breast cancer including initiation, promotion, and progression. During the fifth and sixth decades of life, the production of MLT diminishes, concurrently with an increase in the incidence of breast cancer. Inasmuch as MLT has been demonstrated to have anti-cancer activity, we hypothesized that there may be a causal link between the reduction in MLT production in the pineal gland and the incidence of breast cancer which increases with age. We designed this study to establish whether a truly inverse relationship exists between tissue-isolated mammary tumor growth in young (2 months), adult (12 months), and old (20 months) female Buffalo rats and the decrease in both MLT and the MT1 receptor with age, such that a causal link could be found. Serum MLT levels were measured in both the light and dark phases. A significant 29% decrease in serum MLT levels, measured at the nocturnal peak, was found in the adult and senescent rats (75% decrease) in comparison to that in young rats. In young rats, the nocturnal pineal gland MLT content exceeded daytime levels by 19-fold compared to a sevenfold increase in old mice. Also, the MT1 receptor was found to be significantly lower in the nighttime and early morning in the senescent rat uterus as compared to uteri from young and adult rats. Analysis of the rate of growth in transplanted, tissue-isolated, mammary tumors induced by N-nitroso-n-methyl-urea (NMU) showed a significant increase in the senescent rats, but not in the young or adult rats Additionally, diminished response to the inhibitory action on tumor growth of exogenous MLT was noted in senescent rats such that tumor growth was suppressed by only 33% compared to 48% and 66% in adult and young rats, respectively. The diminution of the response of tumors to exogenous MLT was found to correlate with reduced MT1 receptor expression in senescent compared to young and adult rats. These data suggest that the observed age-associated enhanced growth of tumors is related to the much reduced levels of MLT and its receptor in aged animals which reduce the sensitivity of tumors to inhibition by exogenous MLT.