Circadian regulation of molecular, dietary, and metabolic signaling mechanisms of human breast cancer growth by the nocturnal melatonin signal and the consequences of its disruption by light at night
2011; Wiley; Volume: 51; Issue: 3 Linguagem: Inglês
10.1111/j.1600-079x.2011.00888.x
ISSN1600-079X
AutoresDavid E. Blask, Steven M. Hill, Robert T. Dauchy, Shulin Xiang, Lin Yuan, Tamika Duplessis, Lulu Mao, Erin M. Dauchy, Leonard A. Sauer,
Tópico(s)Dietary Effects on Health
ResumoJournal of Pineal ResearchVolume 51, Issue 3 p. 259-269 REVIEW ARTICLEFree Access Circadian regulation of molecular, dietary, and metabolic signaling mechanisms of human breast cancer growth by the nocturnal melatonin signal and the consequences of its disruption by light at night David E. Blask, David E. Blask Laboratory of Chrono-Neuroendocrine Oncology Department of Structural and Cellular Biology, Tulane University School of Medicine Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, LA, USASearch for more papers by this authorSteven M. Hill, Steven M. Hill Department of Structural and Cellular Biology, Tulane University School of Medicine Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, LA, USASearch for more papers by this authorRobert T. Dauchy, Robert T. Dauchy Laboratory of Chrono-Neuroendocrine Oncology Department of Structural and Cellular Biology, Tulane University School of Medicine Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, LA, USASearch for more papers by this authorShulin Xiang, Shulin Xiang Department of Structural and Cellular Biology, Tulane University School of Medicine Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, LA, USASearch for more papers by this authorLin Yuan, Lin Yuan Department of Structural and Cellular Biology, Tulane University School of Medicine Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, LA, USASearch for more papers by this authorTamika Duplessis, Tamika Duplessis Department of Structural and Cellular Biology, Tulane University School of Medicine Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, LA, USASearch for more papers by this authorLulu Mao, Lulu Mao Department of Structural and Cellular Biology, Tulane University School of Medicine Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, LA, USASearch for more papers by this authorErin Dauchy, Erin Dauchy Laboratory of Chrono-Neuroendocrine Oncology Department of Structural and Cellular Biology, Tulane University School of Medicine Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, LA, USASearch for more papers by this authorLeonard A. Sauer, Leonard A. Sauer Laboratory of Chrono-Neuroendocrine Oncology Department of Structural and Cellular Biology, Tulane University School of MedicineSearch for more papers by this author David E. Blask, David E. Blask Laboratory of Chrono-Neuroendocrine Oncology Department of Structural and Cellular Biology, Tulane University School of Medicine Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, LA, USASearch for more papers by this authorSteven M. Hill, Steven M. Hill Department of Structural and Cellular Biology, Tulane University School of Medicine Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, LA, USASearch for more papers by this authorRobert T. Dauchy, Robert T. Dauchy Laboratory of Chrono-Neuroendocrine Oncology Department of Structural and Cellular Biology, Tulane University School of Medicine Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, LA, USASearch for more papers by this authorShulin Xiang, Shulin Xiang Department of Structural and Cellular Biology, Tulane University School of Medicine Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, LA, USASearch for more papers by this authorLin Yuan, Lin Yuan Department of Structural and Cellular Biology, Tulane University School of Medicine Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, LA, USASearch for more papers by this authorTamika Duplessis, Tamika Duplessis Department of Structural and Cellular Biology, Tulane University School of Medicine Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, LA, USASearch for more papers by this authorLulu Mao, Lulu Mao Department of Structural and Cellular Biology, Tulane University School of Medicine Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, LA, USASearch for more papers by this authorErin Dauchy, Erin Dauchy Laboratory of Chrono-Neuroendocrine Oncology Department of Structural and Cellular Biology, Tulane University School of Medicine Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, LA, USASearch for more papers by this authorLeonard A. Sauer, Leonard A. Sauer Laboratory of Chrono-Neuroendocrine Oncology Department of Structural and Cellular Biology, Tulane University School of MedicineSearch for more papers by this author First published: 02 April 2011 https://doi.org/10.1111/j.1600-079X.2011.00888.xCitations: 131 Address reprint requests to David E. Blask, 1430 Tulane Avenue, SL-49, New Orleans, LA 70112, USA.E-mail: dblask@tulane.edu AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract Abstract: This review article discusses recent work on the melatonin-mediated circadian regulation and integration of molecular, dietary, and metabolic signaling mechanisms involved in human breast cancer growth and the consequences of circadian disruption by exposure to light at night (LAN). The antiproliferative effects of the circadian melatonin signal are mediated through a major mechanism involving the activation of MT1 melatonin receptors expressed in human breast cancer cell lines and xenografts. In estrogen receptor (ERα+) human breast cancer cells, melatonin suppresses both ERα mRNA expression and estrogen-induced transcriptional activity of the ERα via MT1-induced activation of Gαi2 signaling and reduction of 3′,5′-cyclic adenosine monophosphate (cAMP) levels. Melatonin also regulates the transactivation of additional members of the steroid hormone/nuclear receptor super-family, enzymes involved in estrogen metabolism, expression/activation of telomerase, and the expression of core clock and clock-related genes. The anti-invasive/anti-metastatic actions of melatonin involve the blockade of p38 phosphorylation and the expression of matrix metalloproteinases. Melatonin also inhibits the growth of human breast cancer xenografts via another critical pathway involving MT1-mediated suppression of cAMP leading to blockade of linoleic acid uptake and its metabolism to the mitogenic signaling molecule 13-hydroxyoctadecadienoic acid (13-HODE). Down-regulation of 13-HODE reduces the activation of growth factor pathways supporting cell proliferation and survival. Experimental evidence in rats and humans indicating that LAN-induced circadian disruption of the nocturnal melatonin signal activates human breast cancer growth, metabolism, and signaling provides the strongest mechanistic support, thus far, for population and ecological studies demonstrating elevated breast cancer risk in night shift workers and other individuals increasingly exposed to LAN. Introduction The regular alternation in the light/dark cycle over each 24-hr period is the major synchronizer of the endogenous circadian pacemaker located in the suprachiasmatic nuclei (SCN) of the brain in all mammals including humans. The SCN, the neurons of which are most actively firing during the daytime, regulate a variety of hormonal, metabolic, and behavioral responses so that internal physiological and metabolic processes are not only in synchrony with the external environment but also are temporally coordinated and integrated with one another as well [1]. Environmental light is sensed by a small population of intrinsically photosensitive retinal ganglion cells in the retina that contain the blue light-sensitive photopigment melanopsin [2]. From there, information about the light/dark cycle is transmitted to the SCN via the retinohypothalamic tract. A polysynaptic output pathway from the SCN continues to transmit photoperiodic information ultimately to the pineal gland via the brainstem reticular formation, upper thoracic spinal cord, and superior cervical ganglia of the sympathetic chain [3]. During nighttime, substantially reduced inhibitory neuronal activity in the SCN drives the pineal gland to produce high concentrations of the chronobiotic neurohormone melatonin, a potent anti-cancer indoleamine molecule. On the other hand, the pineal synthesis of melatonin during the daytime is almost negligible [4]. High nocturnal blood levels of melatonin are responsible for telling all the cells of the body, including cancer cells, that it is nighttime [5]. Changes in either the length of the day or the timing/phasing of light exposure can compromise SCN activity and/or the pineal gland production of melatonin, a phenomenon referred to as circadian disruption. Another aspect of circadian disruption relates to the ability of exposure of an organism to light at night (LAN) to suppress the amplitude of the nocturnal circadian melatonin signal [6]. The central biological timing mechanism provided by the SCN, including nocturnal melatonin production, has a profound impact on the development and growth of a variety of experimental malignancies in animal models of cancer [6-9]. Circadian disruption caused by either increasing the duration of daily light exposure [10, 11], chronically advancing the phasing of light exposure (chronic jet lag) [12] or LAN-induced suppression of the nocturnal circadian melatonin signal stimulates the development and growth of experimental tumors [10, 11]. Of all the forms of circadian disruption examined thus far, LAN-induced disruption of melatonin production appears to be the most potent promoter of oncogenesis [10, 11]. We now know that most, if not all, normal physiological and metabolic processes as well their pathological sequelae are temporally organized and vary predictably throughout the day and night to accommodate an organism's need to anticipate and adapt to changes in its external environment. The daily rhythmic organization of human physiology and metabolism that is so characteristic of normal cells and tissues also persists during the earlier phases of oncogenesis in malignant neoplasms derived from these same structures. The temporal expression of a multitude of processes governing cancer initiation, growth, progression, invasion/metastasis is regulated by host circadian rhythmic outputs from the central circadian pacemaker in the SCN [13]. At the same time, a number of the very same core molecular clock genes and their respective proteins that operate the master clock in the SCN are coordinately expressed in a circadian manner not only in normal cells in the periphery but also in cancer cells as well [14]. Currently, it is of great interest to cancer biologists that these core clock genes and proteins may be involved in cellular processes such as cell cycle traverse, cell proliferation, DNA damage/repair mechanisms, tumor suppressor activities, cell survival, and apoptosis which themselves exhibit circadian rhythms [15]. Furthermore, it is clear that the central circadian system and perhaps even peripheral clock mechanisms are involved in the regulation of intermediary metabolism [16]. A major question in circadian cancer biology is how the central circadian pacemaker (i.e., SCN) transmits biological timing information to diverse and remote peripheral locations of cancer cells embedded within their microenvironment for the circadian organization of cell proliferation and tumor growth. Also, how does the central circadian timing system influence the regulatory interactions between signal transduction, transcriptional activity, intermediary metabolism, and cell proliferation in tumors? Moreover, what role(s) do peripheral clock-controlled genes (CCGs) within cancer cells play in the daily organization of cancer cell proliferation and how are these peripheral circadian cancer clock mechanisms integrated and coordinated with central clock regulation of tumor growth processes? In this review article, we will focus on some of the most current work, primarily from our own laboratories, on the role of the nocturnal melatonin signal in the regulation of signal transduction, transcriptional activity, CCG gene expression, dietary/metabolic signaling, and proliferation primarily in human breast cancer cells in vitro and in tissue-isolated human breast cancer xenografts in vivo. We will also discuss the consequences of circadian disruption of the melatonin signal by LAN on breast cancer growth processes to provide some initial answers to these questions posed above. Melatonin inhibition of human breast cancer cell proliferation Melatonin's anticancer effects appear to be favorably disposed toward the suppression of cell proliferation. A physiological peak nighttime serum value of 1 nm in humans significantly and directly suppresses the proliferation of both estrogen receptor α-positive (ERα+) human breast cancer cell lines (i.e., MCF-7, T47D, ZR-75-1) and at least one estrogen receptor α-negative (ERα−) (i.e., MDA-MB-468) cell line in vitro by delaying and slowing the progression of cells through the cell cycle [7, 17-19]. These growth-inhibitory actions of melatonin, however, exhibit a bell-shaped dose–response pattern with nocturnal physiological concentrations maximally inhibiting proliferation, while higher or lower concentrations exert little if any effect on ERα+ MCF-7 breast cancer cells [17]. Melatonin's regulation of the cellular redox state and the maintenance of a reducing intracellular environment are critical for physiological melatonin's antiproliferative effects to occur in ERα+ MCF-7 breast cancer cells [7]. With the exception of MDA-MB-468 cells, melatonin fails to inhibit the proliferation of most ERα− human breast cancer cell lines such as MDA-MB-231, MDA-MB-330, or BT-20 [19]. Interestingly, physiological as well as pharmacological levels of melatonin suppress the proliferation and growth of tissue-isolated ERα− and progesterone receptor negative (PR−) human breast cancer xenografts in nude rats via an MT1 receptor-mediated mechanism [20]. The antiproliferative actions of melatonin have been confirmed by numerous laboratories on human breast cancer cells in vitro as well as in other human cancer cell types (i.e., prostate, ovary, endometrium, liver, colon, placenta, bone, etc.) [7]. Melatonin receptor-mediated melatonin suppression of signal transduction and its impact on gene expression in human breast cancer cells Several groups have demonstrated that melatonin binds to and activates MT1 and MT2 G protein-coupled receptors that, in turn, activate a number of G proteins including Gαi2, Gαi3, Gαq, and Gα11 in a variety of tissues [21]. The activated MT1 receptor mediates the oncostatic actions of melatonin in ERα+ MCF-7 human breast cancer cells and is coupled to Gαi2, Gαi3, Gαq, and Gα11 in this cell line. The growth-inhibitory effects of melatonin in breast cancer cells are reversed by nonselective melatonin MT1 and MT2 receptor antagonists while overexpression of the MT1 receptor in human breast cancer cells significantly enhances both the in vitro and in vivo inhibitory response of tumor cells to melatonin [22, 23]. Furthermore, confocal microscopic analysis reveals that the MT1 receptor is localized to the MCF-7 cell membrane and that some MT1 receptors colocalize with caveolin-1, a key protein in caveolae (lipid rafts) membrane-associated signaling platform [24]. Immunohistochemical analysis of 50 breast tumor biopsy specimens demonstrated a significant positive correlation between MT1 receptor and ERα expression [19]. Although MT2 receptors are not detectable in MCF-7 breast cancer cells in culture [25], they are expressed but are apparently nonfunctional in tissue-isolated ERα− MCF-7 human breast cancer xenografts [26]. Melatonin, at physiological nocturnal blood concentrations, modulates the transcriptional activity of ERα and other nuclear receptors in human breast cancer cells That there is an important interplay between the melatonin and estrogen signaling pathways was first indicated by the fact that melatonin could suppress the estrogen-induced proliferation of human breast cancer cells in culture [27, 28]. Subsequently, melatonin was shown to not only suppress ERα mRNA expression [29] but also estrogen-induced transcriptional activity of the ERα as well [25]. This latter effect down-regulates the expression of a number of mitogenic proteins and pathways including the anti-apoptotic protein Bcl-2, while inducing the expression of growth-inhibitory and apoptotic pathways including TGF-α and Bax [25]. The inhibitory action of melatonin on ERα transcriptional activity is mediated via the activation of Gαi2 signaling prompting a decrease in 3′,5′-cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) levels that culminate in decreased phosphorylation of the PKA-sensitive S263 site on the ERα [26]. These findings that melatonin induces the modulation of ERα transcriptional activity were confirmed by another group who further reported that calmodulin (CaM) was also involved in this process [30], an observation that is consistent with the fact that the PKA pathway can impact Ca++/CaM activity in a number of tissues [31]. In addition to suppressing ERα transcriptional activity, melatonin, via different G proteins, can also modulate the transactivation of some other members of the steroid hormone/nuclear receptor super-family. For example, while melatonin reduces the transcriptional activity of the glucocorticoid receptor (GR), it augments the transcriptional activation of the retinoic acid receptor alpha (RARα) in human breast cancer cells in response to their ligands, via activation of Gαi2 and Gαq proteins, respectively [32]. In addition, melatonin decreases the transcriptional activity of the RA-related orphan receptor alpha (RORα) in human breast cancer cells [33]. Moreover, melatonin potentiates the transcriptional activity of the retinoic X receptor alpha (RARα) and the vitamin D3 receptor (VDR), in response to the specific ligands. It appears, however, that melatonin does not modulate all nuclear receptors inasmuch as neither stimulatory nor inhibitory effects of melatonin on ERβ transcriptional activity have been observed in either human breast cancer cells or in ERβ expressing HEK293 embryonic kidney cells [26]. It is still unclear whether melatonin's modulatory effects on nuclear receptors, particularly ERα, are mediated via direct changes in receptor phosphorylation/dephosphorylation, regulation of coactivator (i.e., CaM, SRC1, etc.), and/or coreppressor phosphorylation. Regardless of the exact mechanism(s), these data clearly demonstrate melatonin's important impact on gene expression in human breast cancer cells by its action on specific signal transduction pathways. Melatonin, at physiological nocturnal blood concentrations, acts as a selective estrogen enzyme modulator (SEEM) in the inhibition of human breast cancer growth During the postmenopausal period, estrogens are locally synthesized in breast tissue from adrenal-derived androgenic precursors by the enzyme aromatase [34]. Aromatase is thought to play an important role in postmenopausal breast cancer by converting androstenedione to estrone/estradiol at sufficient levels to support preneoplastic changes and maintain high breast cancer levels of these estrogens in spite of very low or no circulating levels of estradiol. Other enzymes such as estrogen sulfatase (STS) and 17β-hydroxysteroid dehydrogenase (17β-HSD) convert less active estrogens into more potent forms while estrogen sulfotransferases (EST) catalyze estrogen into their less active sulfated forms. Melatonin at nocturnal physiological circulating concentrations inhibits aromatase, STS and 17β-HSD expression and activity in ER+ MCF-7 human breast cancer cells while at the same time stimulating EST. Furthermore, at pharmacological concentrations, melatonin inhibits aromatase activity and in situ synthesis of estrogens in 7,12-dimethylbenzanthracene (DMBA)-induced rat mammary tumors [35]. The involvement of the MT1 receptor in inhibiting the aromatase pathway is supported by findings that transfection of the MT1 receptor in MCF-7 cells significantly decreases aromatase activity of the cells as compared with vector-transfected cells. The proliferation of estrogen-sensitive MCF-7 cells in an estradiol-free media but in the presence of testosterone is markedly inhibited by melatonin (1 nm) in those cells overexpressing the MT1 receptor than in vector-transfected cells. Furthermore, MT1 receptor transfection alone induces a significant 55% inhibition of aromatase steady-state mRNA expression in comparison to vector-transfected MCF-7 cells while exposure of these cells to melatonin (1 nm) significantly down-regulates aromatase mRNA expression than in vector-transfected cells. Therefore, in addition to its role as a selective estrogen receptor modulator (SERM), melatonin also appears to fulfill the requirements as a SEEM; its functions as both a SERM and SEEM appear to be exerted, at least in part, through an MT1 melatonin receptor-mediated mechanism. Melatonin, at nocturnal physiological blood concentrations, regulates telomerase activity and expression in human breast cancer Telomerase is a specialized ribonucleoprotein DNA that elongates the repeats of short TG-rich sequences onto telomeres which constitute both ends of linear chromosomes in eukaryotic cells. Telomeres are progressively shortened during each cell-cycle division in normal differentiated cells, in which telomerase activity is usually absent or low relative to many cancer cells, providing a signal for cell senescence [36]. In most cancer cells, however, telomerase is activated to avert this limiting step thus providing an additional mechanism for unrestricted proliferative capacity in these cells and malignant tumors through telomere elongation. The expression of telomerase reverse transcriptase (TERT), the telomerase subunit that is the main determinant of enzyme activity, tightly correlates with and is a surrogate for telomerase activation [37, 38]. At pharmacological concentrations administered in the drinking water, melatonin not only inhibits the growth of ERα+ MCF-7 human breast cancer xenografts in nude mice, but it also suppresses telomerase activity, as measured by the Telomerase Repeats Amplification Protocol assay in these tumors as compared with controls. Additionally, melatonin at a physiological concentration (1 nm) also reduces the steady-state expression of both TERT mRNA and the TR subunit mRNA of telomerase in MCF-7 breast cancer cells while a pharmacological concentration (100 nm) causes a substantial reduction in estradiol-induced TERT mRNA expression in these cells as well [39, 40]. Thus, another important mechanism of melatonin's oncostatic action at physiological and pharmacological concentrations in ERα+ human breast cancer cells may relate to its ability to suppress telomerase expression and activation, thus minimizing telomere elongation and setting these cells on a course toward apoptotic cell death. Melatonin, at physiological nocturnal blood concentrations, inhibits human breast cancer cell invasion/metastasis Early work on the antineoplastic effects of melatonin revealed that pinealectomy increased while pharmacological melatonin administration diminished the metastatic spread of solid tumors in rodent models of tumorigenesis [41, 42]. Subsequently, compared with numerous studies devoted to melatonin's suppressive effects on human breast cancer cell proliferation, signal transduction, and transcriptional regulation, only a minimal effort has been targeted toward the potential role of melatonin in breast cancer invasion and metastasis in vitro and in vivo. In one investigation in vitro, physiological concentrations of melatonin (1 nm) significantly reduced the invasive capacity of MCF-7 human breast cancer cells and blocked 17-β-estradiol (E2)-induced MCF-7 cell invasion while enhancing the expression of the adhesion proteins, E-cadherin and β1 integrin [43]. In a study examining the in vivo effect of melatonin on telomerase activity, melatonin treatment also lowered the incidence of metastases in nude mice implanted with MCF-7 xenografts, compared with control-treated mice [39] (see below). In an effort to further assess and elucidate the potential anti-invasive/anti-metastatic actions of melatonin, we employed three different clones of MCF-7 cells with demonstrated high metastatic potential. These included the (i) MCF-7/6 clone derived by serial passages in nude mice, (ii) MCF-7Her2.1 cells stably transfected with and over expressing the Her2-neu/c-erbB2 construct, and (iii) MCF-7CXCR4 cells stably transfected with and over expressing the CXCR4 cytokine G protein-coupled receptor. When expressed at high levels, both the Her2/neu (c-erbB2) and CXCR4 receptors are well known to increase the invasive/metastatic potential of breast cancer cells [44] and to even enhance metastatic homing to bone in the case of the CXCR4 receptor [45]. The invasive capacity of these clones was significantly greater than those of parental MCF-7 cells with MCF-7/6 < MCF-7CXCR4 < MCF-7Her2.1 cells. Exposure of MCF-7Her2.1 cells as well as the other two invasive clones to melatonin (1 or 10 nm) resulted in significant suppression (60–85% decrease) of cell invasion using a transwell assay system and matrigel covered inserts. The anti-invasive response to melatonin was enhanced by over-expression of the MT1 receptor and inhibited by administration of luzindole a nonselective MT1/MT2 receptor antagonist arguing for an MT1 receptor-mediated mechanism of melatonin's anti-invasive action. In many cases, invasion and metastasis in breast cancer cells are driven by enhanced activity of the p38 MAPK signaling pathway leading to elevated expression of the matrix metalloproteinases MMP2 and MMP9 [46]. For example, studies from our laboratory [47] have demonstrated that each of the metastatic MCF-7 clones described above has enhanced expression of the phosphorylated forms of p38 and MMP2 and MMP9. Melatonin administration blocks p38 phosporylation and subsequently MMP2 and MMP9 expression, and in doing so, suppresses breast cancer cell invasion. Although we know these actions are MT1 receptor-mediated, we do not yet know the downstream signaling pathways that link the MT1 receptor to p38, however, we suspect that Rho may be a key factor in this process. Melatonin regulation of circadian clock gene expression in human breast cancer cells A connection between cancer development and the circadian cycle has been demonstrated in hormone-related cancers including breast and prostate cancers through the studies of pilots, flight attendants, and night shift workers who are more likely to have disrupted circadian cycles because of their abnormal work hours [6]. Approximately 15–20% of all mammalian genes are CCGs, indicating extensive circadian gene regulation [48]. The 'clock' mechanism that operates in both the SCN and peripheral cells (including cancer cells) consists of interacting positive and negative feedback loops that regulate the transcription of the clock genes, 12 of which have been identified [49]. The Clock and Bmal1 genes participate in a positive feedback loop, whereas period (Per) and cryptochrome (Cry) genes are involved in a negative feedback loop. A heterodimer of Circadian Locomotor Output Cycles Kaput (CLOCK) and Brain and Muscle Aryl Hydrocarbon Receptor Nuclear Translocator – Like 1 (BMAL1) proteins not only rhythmically activates the transcription of clock genes Per1, Per2, Per3, Cry1, Cry2, and Rev-erbα, but also activates downstream CCGs. The rhythmic expression of BMAL1 is generated via its transcriptional activation by RORα and transcriptional repression by Rev-erbα [50]. We recently reported [51] that elevated expression of RORα1 can enhance BMAL1 transcription and expression in MCF-10A human breast epithelial cells and MCF-7 breast cancer cells and that melatonin blunts the transcriptional activation of the RORα1 blocking its induction of BMAL1 expression. Thus, melatonin, via its MT1 receptor, can directly suppress an important element of the clock mechanism in peripheral tissues, specifically breast epithelial and cancer cells. Recent findings suggest that some CCGs function as tumor suppressors at the systemic, cellular, and molecular levels because of their involvement in cell proliferation, apoptosis (p53, Bax), cell-cycle control (ChK2), and DNA damage response (p53, Breast Cancer [BRCA] 1 & 2, Ku70). A recent study showed that disruption of the Per2 gene is associated with tumor development in mice [52]. We have recently reported that expression of the clock protein (PER2) is lost in human breast cancer, while its re-introduction increases p53 expression and induces apoptosis [51]. The anti-aging protein, Silencing Information Regulator Two family member, SIRT1, has been linked with both the molecular circadian clock and cancer [53, 54]. SIRT1 is a NAD+-dependent class III histone deacetylase that impacts a broad spectrum of cellular processes including gene silencing, DNA 11 repair, apoptosis, cellular metabolism, cellular senescence, and aging. SIRT1 has been reported to bind directly to the CLOCK/BMAL1 heterodimer, promoting deacetylation and degradation of PER2 (a tumor suppressor that interacts with BRCA1). SIRT1 also suppresses the tran
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