RESUMEN

Longevity is a highly variable life history trait and its variation is attributable to both genetic and environmental factors. Exploring well-known environmental factors in a new model system is a useful approach to explore taxonomic variation in plasticity of longevity. We examined responsiveness of the Daphnia pulex clone TCO to potentially related interventions that have been reported to extend lifespan: resveratrol and dietary restriction. First, we examined effects of resveratrol on lifespan and fecundity in TCO which were grown at moderate (12K cells Ankistrodesmus falcatus mL⁻¹) and high (20K cells A. falcatus mL⁻¹) food levels. We found no evidence for lifespan extension by resveratrol, but found a reduction of lifetime fecundity. The effect of resveratrol on fecundity was more pronounced early in life. We then conducted an additional life table to test the effect of dietary restriction on TCO. Surprisingly, reduced food level did not extend the lifespan of TCO, which contrasts with previous studies in D. pulex. Our results suggest that variation in the response to dietary restriction might be more common than previously thought. If resveratrol activates genes involved in the response to dietary restriction, genetic polymorphisms in dietary restriction will influence responses to resveratrol. Thus, this experiment suggests that careful re-examination of resveratrol effects using diverse genotypes is required.

Asunto(s)

Restricción Calórica , Daphnia/crecimiento & desarrollo , Longevidad/efectos de los fármacos , Estilbenos/farmacología , Animales , Clasificación , Daphnia/efectos de los fármacos , Daphnia/genética , Fertilidad/efectos de los fármacos , Estadios del Ciclo de Vida/efectos de los fármacos , Polimorfismo Genético , Reproducción/efectos de los fármacos , Reproducción/genética , Resveratrol

RESUMEN

BACKGROUND: Cancer patients routinely develop symptoms consistent with profound circadian disruption, which causes circadian disruption diminished quality of life. This study was initiated to determine the relationship between the severity of potentially remediable cancer-associated circadian disruption and quality of life among patients with advanced lung cancer. METHODS: We concurrently investigated the relationship between the circadian rhythms of 84 advanced lung cancer patients and their quality of life outcomes as measured by the EORTC QLQ C30 and Ferrans and Powers QLI. The robustness and stability of activity/sleep circadian daily rhythms were measured by actigraphy. Fifty three of the patients in the study were starting their definitive therapy following diagnosis and thirty one patients were beginning second-line therapy. Among the patients who failed prior therapy, the median time between completing definitive therapy and baseline actigraphy was 4.3 months, (interquartile range 2.1 to 9.8 months). RESULTS: We found that circadian disruption is universal and severe among these patients compared to non-cancer-bearing individuals. We found that each of these patient's EORTC QLQ C30 domain scores revealed a compromised capacity to perform the routine activities of daily life. The severity of several, but not all, EORTC QLQ C30 symptom items correlate strongly with the degree of individual circadian disruption. In addition, the scores of all four Ferrans/Powers QLI domains correlate strongly with the degree of circadian disruption. Although Ferrans/Powers QLI domain scores show that cancer and its treatment spared these patients' emotional and psychological health, the QLI Health/Function domain score revealed high levels of patients' dissatisfaction with their health which is much worse when circadian disruption is severe. Circadian disruption selectively affects specific Quality of Life domains, such as the Ferrans/Powers Health/Function domain, and not others, such as EORTC QLQ C30 Physical Domain. CONCLUSIONS: These data suggest the testable possibility that behavioral, hormonal and/or light-based strategies to improve circadian organization may help patients suffering from advanced lung cancer to feel and function better.

Asunto(s)

Ritmo Circadiano , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/psicología , Calidad de Vida , Actigrafía , Adulto , Anciano , Anciano de 80 o más Años , Ritmo Circadiano/fisiología , Femenino , Humanos , Neoplasias Pulmonares/epidemiología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Calidad de Vida/psicología , Encuestas y Cuestionarios

RESUMEN

The circadian clock exists in virtually every cell and regulates key biological processes in cells and tissues. Even in cancer cells, DNA synthesis, cell division and tumor growth are gated by the circadian clock. This study examined the gene expression profiles of transplanted mouse breast tumor cells under normal light-dark (LD) as well as constant dark (DD) conditions. It was found that the overall percentage of rhythmic transcripts in breast tumor tissue was lower than that in normal tissue. Few transcripts had unaltered rhythmic expression patterns under both LD and DD conditions. Most rhythmic transcripts in DD displayed 12h or shorter periods. These results suggest that in addition to the circadian clock control of gene transcription, altering light, feeding, physical activity and other factors characteristically affect the expression of many genes.

Asunto(s)

Biomarcadores de Tumor/genética , Proliferación Celular/efectos de la radiación , Ritmo Circadiano/fisiología , Oscuridad , Regulación Neoplásica de la Expresión Génica/fisiología , Luz , Neoplasias Mamarias Experimentales/genética , Animales , Biomarcadores de Tumor/metabolismo , Femenino , Perfilación de la Expresión Génica , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Endogámicos C3H , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa

RESUMEN

Human breast cancer incidence has seasonal patterns that seem to vary among global populations. The aggregate monthly frequency of breast cancer diagnosis was collected and examined for 2,921,714 breast cancer cases diagnosed across 64 global regions over spans from 2 to 53 years. Breast cancer is consistently diagnosed more often in spring and fall, both in the Northern and Southern Hemispheres, regardless of presumable menopausal status (50). This seasonality is increasingly more prominent as population distance from the equator increases and this latitude dependence is most pronounced among women living in rural areas. Moreover, the overall annual incidence (2005-2006), per 100,000 population, of breast cancer increased as the latitude of population residence increased. These data make it clear that human breast cancer discovery occurs non-randomly throughout each year with peaks near both equinoxes and valleys near both solstices. This stable global breast cancer seasonality has implications for better prevention, more accurate screening, earlier diagnosis, and more effective treatment. This complex latitude-dependent breast cancer seasonality is clearly related to predictable local day/night length changes which occur seasonally. Its mechanism may depend upon seasonal sunlight mediation of vitamin D and seasonal mediation of nocturnal melatonin peak level and duration.

Asunto(s)

Neoplasias de la Mama/epidemiología , Estaciones del Año , Femenino , Humanos , Incidencia

RESUMEN

Life has evolved on this planet with regular daily spans of direct solar energy availability alternating with nocturnal spans of dark. Virtually every earth-borne life form has factored this circadian pattern into its biology to ensure the temporal coordination with its resonating environment, a task essential for its individual survival and that of its species. The first whole genome inspections of mutations in human colon and breast cancer have observed specific retained clock gene mutations. Single nucleotide polymorphisms within the genes of clock, clock-controlled, and melatonin pathways have been found to confer excess cancer risk or protection from cancer. Experimental studies have shown that specific core clock genes (Per2 and Per1) are tumor suppressors because their genetic absence doubles tumor numbers, and decreasing their expression in cancer cells doubles cancer growth rate, whereas their overexpression decreases cancer growth rate and diminishes tumor numbers. Experimental interference with circadian clock function increases cancer growth rate, and clinical circadian disruption is associated with higher cancer incidence, faster cancer progression, and shorter cancer patient survival. Patients with advanced lung cancer suffering greater circadian activity/sleep cycle disruption suffer greater interference with function, greater anxiety and depression, poorer nighttime sleep, greater daytime fatigue, and poorer quality of life than comparable patients who maintain good circadian integration. We must now determine whether strategies known to help synchronize the circadian clocks of normal individuals can do so in advanced cancer patients and whether doing so allows cancer patients to feel better and/or live longer. Several academic laboratories and at least 2 large pharmaceutical firms are screening for small molecules targeting the circadian clock to stabilize its phase and enhance its amplitude and thereby consolidate and coordinate circadian organization, which in turn is likely to help prevent and control human cancer. These drugs and strategies can, in turn, be used to make cancer patients with advanced disease feel and function more normally.

Asunto(s)

Ritmo Circadiano , Neoplasias/prevención & control , Animales , Terapia Conductista , Trastornos Cronobiológicos/etiología , Trastornos Cronobiológicos/prevención & control , Cronoterapia , Humanos , Estilo de Vida , Melatonina/uso terapéutico , Neoplasias/complicaciones , Neoplasias/fisiopatología , Calidad de Vida

RESUMEN

The mammalian core clock genes, Periods (Per1 and Per2), have tumor suppressor properties. Decreased expression of Per1 and Per2 has been reported in several types of human cancers. On the other hand, overexpression of Per1 or Per2 inhibits cancer cell growth in culture. The authors have shown that downregulation of Per1 or Per2 enhances cancer growth in vitro. These genes also regulate the amount of cell proliferation-related molecules, many of which are therapeutic targets. In animals, tumors grow with clear circadian organization, and Per1 and Per2 exert their tumor suppressor functions in a circadian time-dependent manner. Downregulation of Per1 or Per2 increases tumor growth only at certain specific times of the day. Per1 and Per2 differentially regulate tumor growth rhythm in vivo. These data suggest that the therapeutic efficacy of antiproliferation agents depends on the time of day of drug delivery. The optimal times of day may be shifted in tumors that have mutant Period genes.

Asunto(s)

Ritmo Circadiano/genética , Neoplasias Mamarias Experimentales/metabolismo , Proteínas Circadianas Period/genética , Animales , Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular , Ritmo Circadiano/fisiología , Regulación hacia Abajo , Femenino , Regulación Neoplásica de la Expresión Génica , Neoplasias Mamarias Experimentales/genética , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Endogámicos C3H , Proteínas Circadianas Period/antagonistas & inhibidores , Proteínas Circadianas Period/biosíntesis , Fotoperiodo

RESUMEN

Cell cycle progression is tightly regulated. The expressions of cell cycle regulators, the products of which either promote or inhibit cell proliferation, oscillate during each cell cycle. Cellular proliferation and the expression of cell cycle regulators are also controlled by the circadian clock. Disruption of the circadian clock may thereby lead to deregulated cell proliferation. Mammalian Per2 is a core clock gene, the product of which suppresses cancer cell proliferation and tumor growth in vivo and in vitro. Because Per1, another key clock gene, is mutated in human breast cancers, and because its clock functions are similar and complementary to those of Per2, we have studied its role in modulating breast cancer cell proliferation and tumor growth. We find that breast cancer growth rate is gated by the circadian clock with two daily peaks and troughs, and that they are coupled to the daily expression patterns of clock-controlled genes that regulate cell proliferation. Down-regulation of the expression of tumor Per1 increases cancer cell growth in vitro and tumor growth in vivo by enhancing the circadian amplitude of the two daily tumor growth peaks. The data of the study suggest Per1 has tumor-suppressor function that diminishes cancer proliferation and tumor growth, but only at specific times of day.

Asunto(s)

Ritmo Circadiano/genética , Neoplasias Mamarias Experimentales/genética , Neoplasias Mamarias Experimentales/patología , Proteínas Circadianas Period/genética , Animales , Secuencia de Bases , Línea Celular Tumoral , Proliferación Celular , Ritmo Circadiano/fisiología , Proteínas de Unión al ADN/genética , Regulación hacia Abajo , Femenino , Humanos , Hígado/fisiopatología , Neoplasias Mamarias Experimentales/fisiopatología , Ratones , Ratones Endogámicos C3H , Trasplante de Neoplasias , Proteínas Circadianas Period/antagonistas & inhibidores , Proteínas Circadianas Period/fisiología , Fotoperiodo , ARN Interferente Pequeño/genética , Factores de Transcripción/genética , Transfección

RESUMEN

Proliferation of intestinal epithelial cells is rhythmic throughout the day. This temporal organization occurs through the interaction between the endogenous peripheral circadian clock and pathways controlling cell cycle progression. Per2, a core clock gene with tumour suppresser function, is critical to clock function and to the regulation of cellular proliferation. Circadian disruption, which increases colon cancer incidence, may do so by deregulating clock controlled epithelial cell proliferation. Increased expression of beta-catenin is a contributing cause of most familial and spontaneous human colon cancer and the cause of multiple intestinal neoplasia of the Apc(Min/+) mouse. Here we report that increased beta-catenin destabilizes PER2 clock protein by inducing beta-TrCP, an F-box protein of SCF ubiquitin E3 ligase. In the intestinal mucosa of the Apc(Min/)(+) mouse, the decrease in PER2 protein levels is associated with altered circadian rhythms of clock genes, Per1 and Per2, and clock controlled genes, Dbp and Wee1. These findings suggest that disruption of the peripheral intestinal circadian clock may be intimately involved in beta-catenin induced intestinal epithelial neoplastic transformation in both mouse and man.

Asunto(s)

Proteínas de Ciclo Celular/metabolismo , Ritmo Circadiano/genética , Mucosa Intestinal/metabolismo , Proteínas Nucleares/metabolismo , Transactivadores/genética , Factores de Transcripción/metabolismo , beta Catenina/metabolismo , Proteínas con Repetición de beta-Transducina/metabolismo , Poliposis Adenomatosa del Colon/metabolismo , Animales , Proteínas CLOCK , Regulación hacia Abajo , Células HCT116 , Humanos , Ratones , Ratones Endogámicos C57BL , Actividad Motora , Proteínas Circadianas Period , Procesamiento Proteico-Postraduccional , Estabilidad Proteica

RESUMEN

Purpose Per2, a core circadian clock gene, has tumor suppressor properties and is mutated or down regulated in human breast cancers. We have manipulated the expression of this gene in vitro and in vivo to more fully understand how the Per2 clock gene product affects cancer growth. Methods We used siRNA and shRNA to down regulate Per2 expression in vitro and in vivo and measured cancer cell proliferation, tumor growth rate and several molecular pathways relevant to cancer growth and their circadian organizations. All statistical tests were two-sided. Results Down regulation of functional Per2 gene expression increases Cyclin D and Cyclin E levels and doubles in vitro breast cancer cell proliferation (P < 0.05). Down regulation of Per2 also accelerates in vivo tumor growth and doubles the daily amplitude of the tumor growth rhythm (P < 0.05). Conclusions The clock gene Per2 exerts its tumor suppressor function in a circadian time dependent manner. Therefore, Per2 and perhaps other clock genes represent a new class of potential therapeutic targets whose manipulation will modulate cancer growth and cancer cell proliferation.

Asunto(s)

Proteínas de Ciclo Celular/genética , Ritmo Circadiano/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Mamarias Experimentales/genética , Proteínas Nucleares/genética , Factores de Transcripción/genética , Animales , Western Blotting , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Proliferación Celular , Ciclina D , Ciclina E/biosíntesis , Ciclinas/biosíntesis , Regulación hacia Abajo , Femenino , Neoplasias Mamarias Experimentales/metabolismo , Ratones , Ratones Endogámicos C3H , Proteínas Nucleares/metabolismo , Proteínas Circadianas Period , ARN Interferente Pequeño , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Transcripción/metabolismo , Transfección

RESUMEN

Colorectal cancer risk is increased in shift workers with presumed circadian disruption. Intestinal epithelial cell proliferation is gated throughout each day by the circadian clock. Period 2 (Per2) is a key circadian clock gene. Per2 mutant (Per2(m/m)) mice show an increase in lymphomas and deregulated expression of cyclin D and c-Myc genes that are key to proliferation control. We asked whether Per2 clock gene inactivation would accelerate intestinal and colonic tumorigenesis. The effects of PER2 on cell proliferation and beta-catenin were studied in colon cancer cell lines by its down-regulation following RNA interference. The effects of Per2 inactivation in vivo on beta-catenin and on intestinal and colonic polyp formation were studied in mice with Per2 mutation alone and in combination with an Apc mutation using polyp-prone Apc(Min/+) mice. Down-regulation of PER2 in colon cell lines (HCT116 and SW480) increases beta-catenin, cyclin D, and cell proliferation. Down-regulation of beta-catenin along with Per2 blocks the increase in cyclin D and cell proliferation. Per2(m/m) mice develop colonic polyps and show an increase in small intestinal mucosa beta-catenin and cyclin D protein levels compared with wild-type mice. Apc(Min/+)Per2(m/m) mice develop twice the number of small intestinal and colonic polyps, with more severe anemia and splenomegaly, compared with Apc(Min/+) mice. These data suggest that Per2 gene product suppresses tumorigenesis in the small intestine and colon by down-regulation of beta-catenin and beta-catenin target genes, and this circadian core clock gene may represent a novel target for colorectal cancer prevention and control.

Asunto(s)

Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Neoplasias del Colon/patología , Genes APC , Mutación , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , beta Catenina/metabolismo , Animales , Línea Celular Tumoral , Proliferación Celular , Ritmo Circadiano , Colon/patología , Neoplasias del Colon/genética , Pólipos del Colon/patología , Ciclina D , Ciclinas/metabolismo , Modelos Animales de Enfermedad , Regulación hacia Abajo , Humanos , Mucosa Intestinal/patología , Pólipos Intestinales/patología , Ratones , Invasividad Neoplásica/genética , Proteínas Circadianas Period , Interferencia de ARN , beta Catenina/genética