Hill Steven M, Cheng Chi, Yuan Lin, Mao Lulu, Jockers Rolf, Dauchy Bob, Blask David E
Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, Louisiana, USA.
Curr Aging Sci. 2013 Feb;6(1):125-33. doi: 10.2174/1874609811306010016.
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.
松果体激素褪黑素（MLT）具有强大的抗乳腺癌活性，其作用主要通过MT1受体介导，并随后调节包括cAMP/PKA、Erk/MAPK、p38和Ca2+/钙调蛋白在内的下游信号通路。此外，通过MT1途径，MLT可以抑制一些促有丝分裂核受体的转录活性，包括ERα、GR和RORα，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。文献综述支持这样一种观点，即MLT通过其MT1受体可以抑制乳腺癌的各个阶段包括起始、促进和进展。在生命的第五和第六个十年中，MLT的分泌减少，同时乳腺癌的发病率增加。鉴于MLT已被证明具有抗癌活性，我们推测松果体中MLT分泌的减少与随年龄增长而增加的乳腺癌发病率之间可能存在因果关系。我们设计了这项研究，以确定在年轻（2个月）、成年（12个月）和老年（20个月）雌性布法罗大鼠中，组织分离的乳腺肿瘤生长与MLT和MT1受体随年龄的减少之间是否真的存在反比关系，以便能够找到因果联系。在光照和黑暗阶段都测量了血清MLT水平。与年轻大鼠相比，在成年和衰老大鼠中（减少75%），在夜间峰值时测量的血清MLT水平显著降低了29%。在年轻大鼠中，夜间松果体MLT含量比白天水平高出19倍，而老年小鼠仅增加了7倍。此外，与年轻和成年大鼠的子宫相比，在衰老大鼠子宫的夜间和清晨发现MT1受体显著降低。对由N-亚硝基-N-甲基脲（NMU）诱导的移植、组织分离的乳腺肿瘤生长速率的分析表明，衰老大鼠中有显著增加，但年轻或成年大鼠中没有。此外，在衰老大鼠中注意到对外源性MLT对肿瘤生长抑制作用的反应减弱，使得肿瘤生长仅被抑制33%，而成年和年轻大鼠分别为48%和66%。发现肿瘤对外源性MLT反应的减弱与衰老大鼠中MT1受体表达的降低有关，而年轻和成年大鼠中MT1受体表达较高。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及其受体水平大幅降低有关，这降低了肿瘤对外源性MLT抑制的敏感性。
