RESUMEN
Prostate cancer, as one of the most prevalent malignancies in males, exhibits an approximate 5-year survival rate of 95% in advanced stages. A myriad of molecular events and mutations, including the accumulation of oncometabolites, underpin the genesis and progression of this cancer type. Despite growing research demonstrating the pivotal role of oncometabolites in supporting various cancers, including prostate cancer, the root causes of their accumulation, especially in the absence of enzymatic mutations, remain elusive. Consequently, identifying a tangible therapeutic target poses a formidable challenge. In this review, we aim to delve deeper into the implications of oncometabolite accumulation in prostate cancer. We center our focus on the consequential epigenetic alterations and impacts on cancer stem cells, with the ultimate goal of outlining novel therapeutic strategies.
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Neoplasias , Neoplasias de la Próstata , Masculino , Humanos , Epigénesis Genética , Microambiente Tumoral , Neoplasias de la Próstata/genética , Neoplasias/patología , Mutación , Células Madre Neoplásicas/patologíaRESUMEN
BACKGROUND: Adipose tissue has gained attention due to its potential paracrine role. Periprostatic adipose tissue surrounds the prostate and the prostatic urethra, and it is an essential player in prostate cancer progression. Since obesity is directly related to human tumor progression, and adipose tissue depots are one of the significant components of the tumor microenvironment, the molecular mediators of the communication between adipocytes and epithelial cells are in the spotlight. Although periprostatic white adipose tissue contributes to prostate cancer progression, brown adipose tissue (BAT), which has beneficial effects in metabolic pathologies, has been scarcely investigated concerning cancer progression. Given that adipose tissue is a target of androgen signaling, the actual role of androgen removal on the periprostatic adipose tissue was the aim of this work. METHODS: Surgical castration of the transgenic adenocarcinoma of the mouse prostate (TRAMP) was employed. By histology examination and software analysis, WAT and BAT tissue was quantified. 3T3-like adipocytes were used to study the role of Casodex® in modifying adipocyte differentiation and to investigate the function of the secretome of adipocytes on the proliferation of androgen-dependent and independent prostate cancer cells. Finally, the role of cell communication was assayed by TRAMP-C1 xenograft implanted in the presence of 3T3-like adipocytes. RESULTS: Androgen removal increases brown/beige adipose tissue in the fat immediately surrounding the prostate glands of TRAMP mice, concomitant with an adjustment of the metabolism. Castration increases body temperature, respiratory exchange rate, and energy expenditure. Also, in vitro, it is described that blocking androgen signaling by Casodex® increases the uncoupling protein 1 (UCP1) marker in 3T3-like adipocytes. Finally, the effect of brown/beige adipocyte secretome was studied on the proliferation of prostate cancer cells in vivo and in vitro. The secretome of brown/beige adipocytes reduces the proliferation of prostate cancer cells mediated partly by the secretion of extracellular vesicles. CONCLUSIONS: Consequently, we concluded that hampering androgen signaling plays a crucial role in the browning of the periprostatic adipose tissue. Also, the presence of brown adipocytes exhibits the opposite effect to that of white adipocytes in vitro regulating processes that govern the mechanisms of cell proliferation of prostate cancer cells. And finally, promoting the browning of adipose tissue in the periprostatic adipose tissue might be a way to handle prostate cancer cell progression. Video Abstract.
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Próstata , Neoplasias de la Próstata , Masculino , Humanos , Ratones , Animales , Andrógenos , Microambiente Tumoral , CastraciónRESUMEN
Nowadays, the study of cell metabolism is a hot topic in cancer research. Many studies have used 2D conventional cell cultures for their simplicity and the facility to infer mechanisms. However, the limitations of bidimensional cell cultures to recreate architecture, mechanics, and cell communication between tumor cells and their environment, have forced the development of other more realistic in vitro methodologies. Therefore, the explosion of 3D culture techniques and the necessity to reduce animal experimentation to a minimum has attracted the attention of researchers in the field of cancer metabolism. Here, we revise the limitations of actual culture models and discuss the utility of several 3D culture techniques to resolve those limitations.
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Técnicas de Cultivo de Célula , Neoplasias , Animales , Técnicas de Cultivo de Célula/métodos , Neoplasias/patología , Respiración de la Célula , Estrés Oxidativo , BiologíaRESUMEN
Angiogenesis is an established prognostic factor in advanced breast cancer, yet response to antiangiogenic therapies in this disease remains highly variable. Noninvasive imaging biomarkers could help identify patients that will benefit from antiangiogenic therapy and provide an ideal tool for longitudinal monitoring, enabling dosing regimens to be altered with real-time feedback. Photoacoustic tomography (PAT) is an emerging imaging modality that provides a direct readout of tumor hemoglobin concentration and oxygenation. We hypothesized that PAT could be used in the longitudinal setting to provide an early indication of response or resistance to antiangiogenic therapy. To test this hypothesis, PAT was performed over time in estrogen receptor-positive and estrogen receptor-negative breast cancer xenograft mouse models undergoing treatment with the antiangiogenic bevacizumab as a single agent. The cohort of treated tumors, which were mostly resistant to the treatment, contained a subset that demonstrated a clear survival benefit. At endpoint, the PAT data from the responding subset showed significantly lower oxygenation and higher hemoglobin content compared with both resistant and control tumors. Longitudinal analysis revealed that tumor oxygenation diverged significantly in the responding subset, identifying early treatment response and the evolution of different vascular phenotypes between the subsets. Responding tumors were characterized by a more angiogenic phenotype when analyzed with IHC, displaying higher vessel density, yet poorer vascular maturity and elevated hypoxia. Taken together, our findings indicate that PAT shows promise in providing an early indication of response or resistance to antiangiogenic therapy. SIGNIFICANCE: Photoacoustic assessment of tumor oxygenation is a noninvasive early indicator of response to bevacizumab therapy, clearly distinguishing between control, responding, and resistant tumors within just a few weeks of treatment.
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Neoplasias de la Mama , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Bevacizumab/farmacología , Bevacizumab/uso terapéutico , Neoplasias de la Mama/irrigación sanguínea , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Hemoglobinas , Humanos , Ratones , Neovascularización Patológica/diagnóstico por imagen , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/genética , Receptores de Estrógenos , TomografíaRESUMEN
Prostate cancer is the second leading cause of cancer in men across the globe. The prostate gland accounts for some unique glycolytic metabolic characteristics, which causes the metabolic features of prostate tumor initiation and progression to remain poorly characterized. The mitochondrial superoxide dismutase (SOD2) is one of the major redox metabolism regulators. This study points out SOD2 as one major regulator for both redox and glycolytic metabolism in prostate cancer. SOD2 overexpression increases glucose transporter GLUT-1 and glucose uptake. This is not an insulin-mediated effect and seems to be sex-dependent, being present in male mice only. This event concurs with a series of substantial metabolic rearrangements at cytoplasmic and mitochondrial level. A concomitant decrease in glycolytic and pentose phosphate activity, and an increase in electron transfer in the mitochondrial electronic chain, were observed. The Krebs Cycle is altered to produce amino-acid intermediates by decreasing succinate dehydrogenase. This in turn generates a 13-fold increase in the oncometabolite succinate. The protein energy sensor AMPK is decreased at basal and phosphorylated levels in response to glucose deprivation. Finally, preliminary results in prostate cancer patients indicate that glandular areas presenting high levels of SOD2 show a very strong correlation with GLUT-1 protein levels (R2 = 0.287 p-value < 0.0001), indicating that in patients there may exist an analogous phenomenon to those observed in cell culture and mice.
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During food processing and storage, and in tissues and fluids under physiological conditions, the Maillard reaction occurs. During this reaction, reactive 1,2-dicarbonyl compounds arise as intermediates that undergo further reactions to form advanced glycation end products (AGEs). Diet is the primary source of exogenous AGEs. Endogenously formed AGEs have been proposed as a risk factor in the pathogenesis of diet-related diseases such as diabetes, insulin resistance, cardiovascular diseases, or chronic disease. AGEs may differently contribute to the diet-related exacerbation of oxidative stress, inflammation, and protein modifications. Here, to understand the contribution of each compound, we tested individually, for the first time, the effect of five 1,2-dicarbonyl compounds 3-deoxyglucosone (3-DG), 3-deoxygalactosone (3-DGal), 3,4-dideoxyglucosone-3-ene (3,4-DGE), glyoxal (GO), and methylglyoxal (MGO) and four different glycated amino acids N-ε-(carboxyethyl)lysine (CEL), N-ε-(carboxymethyl)lysine (CML), methylglyoxal-derived hydroimidazolone-1 (MG-H1), and pyrraline (Pyrr) in a cell line of human keratinocytes (HaCaT). We found that most of the glycated amino acids, i.e., CEL, CML, and MG-H1, did not show any cytotoxicity. At the same time, 1,2-dicarbonyl compounds 3-DGal, 3,4-DGE, GO, and MGO increased the production of reactive oxygen species and induced cell death. MGO induced cell death by apoptosis, whereas 3-DGal and 3,4-DGE induced nuclear translocation of the proinflammatory NF-κB transcription pathway, and the activation of the pyroptosis-related NLRP3 inflammasome cascade. Overall, these results demonstrate the higher toxic impact of 1,2-dicarbonyl compounds on mucosal epithelial cells when compared to glycated amino acids and the selective activation of intracellular signaling pathways involved in the crosstalk mechanisms linking oxidative stress to excessive inflammation.
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Apoptosis , Productos Finales de Glicación Avanzada/efectos adversos , Inflamación/tratamiento farmacológico , Queratinocitos/patología , Estrés Oxidativo/efectos de los fármacos , Pironas/efectos adversos , Desoxiglucosa/efectos adversos , Desoxiglucosa/análogos & derivados , Galactosa/efectos adversos , Galactosa/análogos & derivados , Humanos , Técnicas In Vitro , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/patología , Queratinocitos/efectos de los fármacos , Queratinocitos/inmunología , Queratinocitos/metabolismo , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
During the last 25 years we have accomplished great advances in melatonin research, regarding antioxidant or anti-inflammatory functions, oncostatic actions, glucose metabolism regulation or plant physiology, among others. Of course, we should not forget the classical, circadian-related functions of the indole, which has recently brought up new and important findings. All together these new discoveries will likely lead the way in the next decade in terms of melatonin research. This special issue collects some of these new advances focused on different aspects of the indole.
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Melatonina/metabolismo , Animales , Antineoplásicos/farmacología , Antioxidantes/farmacología , Depresores del Sistema Nervioso Central/farmacología , Humanos , Melatonina/farmacologíaRESUMEN
Diets are currently characterized by elevated sugar intake, mainly due to the increased consumption of processed sweetened foods and drinks during the last 40 years. Diet is the main source of advanced glycation endproducts (AGEs). These are toxic compounds formed during the Maillard reaction, which takes place both in vivo, in tissues and fluids under physiological conditions, favored by sugar intake, and ex vivo during food preparation such as baking, cooking, frying or storage. Protein glycation occurs slowly and continuously through life, driving AGE accumulation in tissues during aging. For this reason, AGEs have been proposed as a risk factor in the pathogenesis of diet-related diseases such as diabetes, insulin resistance, cardiovascular diseases, kidney injury, and age-related and neurodegenerative diseases. AGEs are associated with an increase in oxidative stress since they mediate the production of reactive oxygen species (ROS), increasing the intracellular levels of hydrogen peroxide (H2O2), superoxide (O2-), and nitric oxide (NO). The interaction of AGEs with the receptor for AGEs (RAGE) enhances oxidative stress through ROS production by NADPH oxidases inside the mitochondria. This affects mitochondrial function and ultimately influences cell metabolism under various pathological conditions. This short review will summarize all evidence that relates AGEs and ROS production, their relationship with diet-related diseases, as well as the latest research about the use of natural compounds with antioxidant properties to prevent the harmful effects of AGEs on health.
RESUMEN
Neuroindole melatonin, a hormone synthesized during the night mainly-but not exclusively-by the pineal gland of all vertebrates, functions as an adapting signal to the light-dark cycle. Its antioxidant, neuroprotective, anti-inflammatory, and antitumor properties are all well-known and widely reported. Melanoma is one of the most common carcinomas among developed countries and a type of tumor particularly difficult to fight back in medium/advanced stages. In contrast to other types of cancer, influence of melatonin on melanoma has been scarcely investigated. Thus, we have chosen the murine melanoma model B16-F10 cell line to study antiproliferative and antitumoral actions of melatonin. For this purpose, we combined both, cell culture and in vivo models. Melatonin reduced either, growth rate or migration of B16-F10 cells. Furthermore, melanin synthesis was altered by melatonin, promoting its synthesis. Melatonin also induced a G2/M cell cycle arrest and altered the cytoskeletal organization. To corroborate these results, we tested the effect of melatonin in the in vivo model of B16-F10 cell injection in the tail vein, which causes numerous lung metastases. Two different strategies of melatonin administration were used, namely, in drinking water, or daily intraperitoneal injection. However, contrary to what occurred in cell culture, no differences were observed between control and melatonin treated groups. Results obtained led us to conclude that melatonin exerts an antiproliferative and anti-migrating effect on this melanoma model by interfering with the cytoskeleton organization, but this pharmacological effect cannot be translated in vivo as the indole did not prevent metastasis in the murine model, suggesting that further insights into the effects of the indole in melanoma cells should be approached to understand this apparent paradox.
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Proliferación Celular/efectos de los fármacos , Citoesqueleto/efectos de los fármacos , Melanoma Experimental/metabolismo , Melatonina/farmacología , Actinas/genética , Actinas/metabolismo , Animales , Antioxidantes/administración & dosificación , Antioxidantes/farmacología , Catalasa/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Citoesqueleto/genética , Citoesqueleto/metabolismo , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundario , Melaninas/metabolismo , Melanoma Experimental/genética , Melanoma Experimental/patología , Melatonina/administración & dosificación , Ratones Endogámicos C57BL , Superóxido Dismutasa/metabolismo , Tiorredoxinas/metabolismo , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismoRESUMEN
Advanced glycation end products (AGEs) are glycated proteins associated with high dry temperature food processing, coloring and flavor modification of food products. Previous studies on diet-related disease support the role of the glycation products as biomarkers in local and general proinflammatory response. Exogenous and endogenous AGEs are involved in chronic low-level inflammation, which underlies the onset of metabolic syndrome influenced by food intake, there by demonstrating their implication in diet-related pathologies. Although studies have revealed a strong association between the accumulation of AGEs and the occurrence/worsening of metabolic diseases, their routine use for the diagnosis or monitoring of local and general disease has not yet been reported.
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Enfermedad , Productos Finales de Glicación Avanzada/metabolismo , Saliva/metabolismo , Envejecimiento/metabolismo , Animales , Biomarcadores/química , Biomarcadores/metabolismo , Productos Finales de Glicación Avanzada/química , HumanosRESUMEN
Melatonin, N-acetyl-5-methoxytryptamine, is an indole mainly synthesized from tryptophan in the pineal gland and secreted exclusively during the night in all the animals reported to date. While the pineal gland is the major source responsible for this night rise, it is not at all the exclusive production site and many other tissues and organs produce melatonin as well. Likewise, melatonin is not restricted to vertebrates, as its presence has been reported in almost all the phyla from protozoa to mammals. Melatonin displays a large set of functions including adaptation to light: dark cycles, free radical scavenging ability, antioxidant enzyme modulation, immunomodulatory actions or differentiationâ»proliferation regulatory effects, among others. However, in addition to those important functions, this evolutionary 'ancient' molecule still hides further tools with important cellular implications. The major goal of the present review is to discuss the data and experiments that have addressed the relationship between the indole and glucose. Classically, the pineal gland and a pinealectomy were associated with glucose homeostasis even before melatonin was chemically isolated. Numerous reports have provided the molecular components underlying the regulatory actions of melatonin on insulin secretion in pancreatic beta-cells, mainly involving membrane receptors MTNR1A/B, which would be partially responsible for the circadian rhythmicity of insulin in the organism. More recently, a new line of evidence has shown that glucose transporters GLUT/SLC2A are linked to melatonin uptake and its cellular internalization. Beside its binding to membrane receptors, melatonin transportation into the cytoplasm, required for its free radical scavenging abilities, still generates a great deal of debate. Thus, GLUT transporters might constitute at least one of the keys to explain the relationship between glucose and melatonin. These and other potential mechanisms responsible for such interaction are also discussed here.
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Glucosa/metabolismo , Melatonina/metabolismo , Animales , Transporte Biológico , Membrana Celular/metabolismo , Metabolismo Energético , Humanos , Insulina/metabolismo , Glándula Pineal/metabolismo , Transporte de Proteínas , Vesículas Secretoras/metabolismoRESUMEN
OBJECTIVE: Maillard advanced glycation end products (AGEs) are connected with high dry temperature food processing, color and flavor modification of food products. Oral cavity pathology is strongly influenced by dietary intake. The aim of the present paper is to update current data regarding the sources and metabolism of AGEs, their impact on oral cavity tissues, to discuss and suggest new approaches for the early diagnosis and efficient treatment of AGEs-related oral pathology. DESIGN: This paper is a narrative review of the studies discussing AGEs and mainly the dietary AGEs (dAGEs) sources, metabolism, linkage to general diseases, and specifically the oral cavity pathology. The authors used "PUBMED" and MeSH for the finding of English written and published articles concerning AGEs. There were used the next keywords association: "advanced glycation end products- AGEs" AND "Maillard products", "AGEs" AND "diet-related disease, "AGEs" AND "salivary biosensor", "AGEs" AND "metabolic syndrome AGEs", "AGEs" AND "oral pathology", "AGEs" AND "dentin AGEs" OR "periodontal AGEs", "AGEs" AND "diagnosis and monitoring". The authors used free full-text articles to determine the etiology and physiopathology of AGEs, their association with general diseases and oral cavity disease, assessment methods used in biofluids and tissues, AGEs prevention and treatment approaches. Articles concerning AGEs etiology, metabolism and effect in the human body and specific implication in oral pathology were selected. There were no exclusion criteria in what concerns the study design. Studies in other language than English and articles abstracts were excluded. Criteria of inclusion were free full-text articles written in English. Equally human and animal model studies were included. Regarding the date of publication, all subjects concerning glycation products after 1953 (first published article) were included. RESULTS: Evidence show that AGEs are responsible for inducing low intensity chronic inflammation and thereby, for initiating and/or aggravating chronic diseases. Nowadays, research has demonstrated a significant association between AGEs and dental or periodontal pathology. Moreover, salivary AGEs are consistent with the levels of AGEs in other biological fluids and are correlated with the general and oral pathology. CONCLUSIONS: Assessment of salivary AGEs could be a reliable tool for early diagnosis and monitoring diet-related disease.
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Productos Finales de Glicación Avanzada/metabolismo , Enfermedades Estomatognáticas/metabolismo , Animales , HumanosRESUMEN
Glucose, chief metabolic support for cancer cell survival and growth, is mainly imported into cells by facilitated glucose transporters (GLUTs). The increase in glucose uptake along with tumor progression is due to an increment of facilitative glucose transporters as GLUT1. GLUT1 prevents cell death of cancer cells caused by growth factors deprivation, but there is scarce information about its role on the damage caused by glucose deprivation, which usually occurs within the core of a growing tumor. In prostate cancer (PCa), GLUT1 is found in the most aggressive tumors, and it is regulated by androgens. To study the response of androgen-sensitive and insensitive PCa cells to glucose deprivation and the role of GLUT1 on survival mechanisms, androgen-sensitive LNCaP and castration-resistant LNCaP-R cells were employed. Results demonstrated that glucose deprivation induced a necrotic type of cell death which is prevented by antioxidants. Androgen-sensitive cells show a higher resistance to cell death triggered by glucose deprivation than castration-resistant cells. Glucose removal causes an increment of H2O2, an activation of androgen receptor (AR) and a stimulation of AMP-activated protein kinase activity. In addition, glucose removal increases GLUT1 production in androgen sensitive PCa cells. GLUT1 ectopic overexpression makes PCa cells more resistant to glucose deprivation and oxidative stress-induced cell death. Under glucose deprivation, GLUT1 overexpressing PCa cells sustains mitochondrial SOD2 activity, compromised after glucose removal, and significantly increases reduced glutathione (GSH). In conclusion, androgen-sensitive PCa cells are more resistant to glucose deprivation-induced cell death by a GLUT1 upregulation through an enhancement of reduced glutathione levels.
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Transportador de Glucosa de Tipo 1/genética , Estrés Oxidativo/genética , Neoplasias de la Próstata Resistentes a la Castración/genética , Superóxido Dismutasa/genética , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Glucosa/metabolismo , Transportador de Glucosa de Tipo 1/metabolismo , Glutatión/metabolismo , Humanos , Peróxido de Hidrógeno/química , Masculino , Próstata/metabolismo , Próstata/patología , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/patología , Receptores Androgénicos/genética , Superóxido Dismutasa/metabolismoRESUMEN
T lymphocytes, from their first encounter with their specific antigen as naïve cell until the last stages of their differentiation, in a replicative state of senescence, go through a series of phases. In several of these stages, T lymphocytes are subjected to exponential growth in successive encounters with the same antigen. This entire process occurs throughout the life of a human individual and, earlier, in patients with chronic infections/pathologies through inflammatory mediators, first acutely and later in a chronic form. This process plays a fundamental role in amplifying the activating signals on T lymphocytes and directing their clonal proliferation. The mechanisms that control cell growth are high levels of telomerase activity and maintenance of telomeric length that are far superior to other cell types, as well as metabolic adaptation and redox control. Large numbers of highly differentiated memory cells are accumulated in the immunological niches where they will contribute in a significant way to increase the levels of inflammatory mediators that will perpetuate the new state at the systemic level. These levels of inflammation greatly influence the process of T lymphocyte differentiation from naïve T lymphocyte, even before, until the arrival of exhaustion or cell death. The changes observed during lymphocyte differentiation are correlated with changes in cellular metabolism and these in turn are influenced by the inflammatory state of the environment where the cell is located. Reactive oxygen species (ROS) exert a dual action in the population of T lymphocytes. Exposure to high levels of ROS decreases the capacity of activation and T lymphocyte proliferation; however, intermediate levels of oxidation are necessary for the lymphocyte activation, differentiation, and effector functions. In conclusion, we can affirm that the inflammatory levels in the environment greatly influence the differentiation and activity of T lymphocyte populations. However, little is known about the mechanisms involved in these processes. The elucidation of these mechanisms would be of great help in the advance of improvements in pathologies with a large inflammatory base such as rheumatoid arthritis, intestinal inflammatory diseases, several infectious diseases and even, cancerous processes.
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Diferenciación Celular/inmunología , Proliferación Celular , Especies Reactivas de Oxígeno , Linfocitos T , Animales , Humanos , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/patología , Oxidación-Reducción , Especies Reactivas de Oxígeno/inmunología , Especies Reactivas de Oxígeno/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Linfocitos T/patologíaRESUMEN
One of the hallmarks of cancer cells is the increased ability to acquire nutrients, particularly glucose and glutamine. Proliferating cells need precursors for cell growth and NADPH reducing equivalents for survival. The principal responsible for glucose uptake is facilitative glucose transporters (GLUTs), which usually are overexpressed in cancer cells. Besides their role in glucose uptake, GLUT transporters are able to transport other compounds such as dehydroascorbic acid or uric acid. They play a major role in tumor progression and cellular processes such as regulated cell death. The prostate gland has the particular characteristic of being more glycolytic than other non-pathological tissues given an accumulation of citrate in the seminal fluid and the inhibition of m-aconitase that affects to tricarboxylic acid cycle. In prostate cancer (PCa), androgens increase glucose uptake, upregulate GLUT transporters such as GLUT1 and GLUT3 and stimulate AMP-activated protein kinase pathway, suggesting a possible connection between glycolytic and androgenic signaling. Interestingly, diabetes is not a risk factor for PCa, as it is in other cancers, while insulin stimulates progression and insulin-like growth factor 1 pathway plays an important role in PCa progression. It was recently found that PCa cells overexpress GLUT4 and, more importantly, that it seems to be related to the castration-resistant prostate cancer (CRPC) phenotype, although little is known about its participation in tumor progression. This review will focus on the role of GLUT transporters along with PCa progression, and the involvement of GLUT4 on CRPC phenotype transition would be considered.
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Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Humanos , MasculinoRESUMEN
The pineal neuroindole melatonin exerts an exceptional variety of systemic functions. Some of them are exerted through its specific membrane receptors type 1 and type 2 (MT1 and MT2) while others are mediated by receptor-independent mechanisms. A potential transport of melatonin through facilitative glucose transporters (GLUT/SLC2A) was proposed in prostate cancer cells. The prostate cells have a particular metabolism that changes during tumor progression. During the first steps of carcinogenesis, oxidative phosphorylation is reactivated while the switch to the "Warburg effect" only occurs in advanced tumors and in the metastatic stage. Here, we investigated whether melatonin might change prostate cancer cell metabolism. To do so, 13C stable isotope-resolved metabolomics in androgen sensitive LNCaP and insensitive PC-3 prostate cancer cells were employed. In addition to metabolite 13C-labeling, ATP/AMP levels, and lactate dehydrogenase or pentose phosphate pathway activity were measured. Melatonin reduces lactate labeling in androgen-sensitive cells and it also lowers 13C-labeling of tricarboxylic acid cycle metabolites and ATP production. In addition, melatonin reduces lactate 13C-labeling in androgen insensitive prostate cancer cells. Results demonstrated that melatonin limits glycolysis as well as the tricarboxylic acid cycle and pentose phosphate pathway in prostate cancer cells, suggesting that the reduction of glucose uptake is a major target of the indole in this tumor type.
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Adenosina Trifosfato/biosíntesis , Glucólisis/efectos de los fármacos , Melatonina/administración & dosificación , Neoplasias de la Próstata/tratamiento farmacológico , Adenosina Trifosfato/genética , Andrógenos/metabolismo , Isótopos de Carbono/química , Línea Celular Tumoral , Glucosa/metabolismo , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Humanos , Marcaje Isotópico , Masculino , Metabolómica , Fosforilación Oxidativa/efectos de los fármacos , Próstata/efectos de los fármacos , Próstata/metabolismo , Próstata/patología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Receptor de Melatonina MT1/genética , Receptor de Melatonina MT2/genéticaRESUMEN
Melatonin is a well-known, nighttime-produced indole found in bacteria, eukaryotic unicellulars, animals or vascular plants. In vertebrates, melatonin is the major product of the pineal gland, which accounts for its increase in serum during the dark phase, but it is also produced by many other organs and cell types. Such a wide distribution is consistent with its multiple and well-described functions which include from the circadian regulation and adaptation to seasonal variations to immunomodulatory and oncostatic actions in different types of tumors. The discovery of its antioxidant properties in the early 1990s opened a new field of potential protective functions in multiple tissues. A special mention should be made regarding the nervous system, where the indole is considered a major neuroprotector. Furthermore, mitochondria appear as one of the most important targets for the indole's protective actions. Melatonin's mechanisms of action vary from the direct molecular interaction with free radicals (free radical scavenger) to the binding to membrane (MLT1A and MLT1B) or nuclear receptors (RZR/RORα). Receptor binding has been associated with some, but not all of the indole functions reported to date. Recently, two new mechanisms of cellular uptake involving the facilitative glucose transporters GLUT/SLC2A and the proton-driven oligopeptide transporter PEPT1/2 have been reported. Here we discuss the potential importance that these newly discovered transport systems could have in determining the actions of melatonin, particularly in the mitochondria. We also argue the relative importance of passive diffusion vs active transport in different parts of the cell.
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Antioxidantes/farmacología , Radicales Libres/metabolismo , Melatonina/farmacología , Mitocondrias/metabolismo , Animales , Transporte Biológico , Humanos , Mitocondrias/efectos de los fármacosRESUMEN
Accumulating evidence suggests that natural bioactive compounds, alone or in combination with traditional chemotherapeutic agents, could be used as potential therapies to fight cancer. In this study, we employed four natural bioactive compounds (curcumin, resveratrol, melatonin, and silibinin) and studied their role in redox control and ability to promote apoptosis in androgen sensitive and insensitive prostate cancer cells. Here is shown that curcumin and resveratrol promote ROS production and induce apoptosis in LNCaP and PC-3. An increase in reactive species is a trigger event in curcumin-induced apoptosis and a consequence of resveratrol effects on other pathways within these cells. Moreover, here we demonstrated that these four compounds affect differently one of the main intracellular redox regulator, the thioredoxin system. Exposure to curcumin and resveratrol promoted TRX1 oxidation and altered its subcellular location. Furthermore, resveratrol diminished TRX1 levels in PC-3 cells and increased the expression of its inhibitor TXNIP. Conversly, melatonin and silibinin only worked as cytostatic agents, reducing ROS levels and showing preventive effects against TRX oxidation. All together, this work explores the effect of compounds currently tested as chemo-preventive agents in prostate cancer therapy, on the TRX1 redox state and function. Our work shows the importance that the TRX system might have within the differences found in their mechanisms of action. These bioactive compounds trigger different responses and affect ROS production and redox systems in prostate cancer cells, suggesting the key role that redox-related pathways might play in processes like differentiation or survival in prostate cancer.
Asunto(s)
Curcumina/farmacología , Melatonina/farmacología , Neoplasias de la Próstata/metabolismo , Silimarina/farmacología , Estilbenos/farmacología , Tiorredoxinas/metabolismo , Apoptosis , Proteínas Portadoras/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Neoplasias de la Próstata/tratamiento farmacológico , Especies Reactivas de Oxígeno/metabolismo , Resveratrol , SilibinaRESUMEN
Epigenetic modifications, including methylation or acetylation as well as post-transcriptional modifications, are mechanisms used by eukaryotic cells to increase the genome diversity in terms of differential gene expression and protein diversity. Among these modifying enzymes, sirtuins, a class III histone deacetylase (HDAC) enzymes, are of particular importance. Sirtuins regulate the cell cycle, DNA repair, cell survival, and apoptosis, thus having important roles in normal and cancer cells. Sirtuins can also regulate metabolic pathways by changing preference for glycolysis under aerobic conditions as well as glutaminolysis. These actions make sirtuins a major target in numerous physiological processes as well as in other contexts such as calorie restriction-induced anti-aging, cancer, or neurodegenerative disease. Interestingly, melatonin, a nighttime-produced indole synthesized by pineal gland and many other organs, has important cytoprotective effects in many tissues including aging, neurodegenerative diseases, immunomodulation, and cancer. The pleiotropic actions of melatonin in different physiological and pathological conditions indicate that may be basic cellular targeted for the indole. Thus, much research has focused attention on the potential mechanisms of the indole in modulating expression and/or activity of sirtuins. Numerous findings report a rise in activity, especially on SIRT1, in a diversity of cells and animal models after melatonin treatment. This contrasts, however, with data reporting an inhibitory effect of melatonin on this sirtuin in some tumor cells. This review tabulates and discusses the recent findings relating melatonin with sirtuins, particularly SIRT1 and mitochondrial SIRT3, showing the apparent dichotomy with the differential actions documented in normal and in cancer cells.
Asunto(s)
Melatonina/metabolismo , Sirtuinas/metabolismo , Animales , HumanosRESUMEN
Treatment of prostate cancer (PCa), a leading cause of cancer among males, lacks successful strategies especially in advanced, hormone-refractory stages. Some clinical studies have shown an increase in neuroendocrine-like cells parallel to the tumor progression but their exact role is a matter of debate. The prostate is a well-known target for melatonin, which reduces PCa cells proliferation and induces neuroendocrine differentiation. To evaluate the mechanisms underlying the indole effects on neuroendocrine differentiation and its impact on PCa progression, we used a cell culture model (LNCaP) and a murine model (TRAMP). Persistent ERK1/2 activation was found in both, melatonin and androgen-deprived cells. Melatonin blocked nuclear translocation of androgen receptor (AR), thus confirming anti-androgenic actions of the indole. However, using a comparative genome microarray to check the differentially expressed genes in control, melatonin, or androgen-deprived cells, some differences were found, suggesting a more complex role of the indole. By comparing control cells with those treated with melatonin or depleted of androgen, a cluster of 26 differentially expressed genes (±2.5-fold) was found. Kallikreins (KLK)2 and KLK3 (PSA) were dramatically downregulated by both treatments whereas IGFBP3 and IGF1R were up- and downregulated, respectively, in both experimental groups, thus showing a role for IGF in both scenarios. Finally, melatonin prolonged the survival of TRAMP mice by 33% when given at the beginning or at advances stages of the tumor. Serum IGFBP3 was significantly elevated by the indole in early stages of the tumor, confirming in vivo the role of the IGF signaling in the oncostatic action of the indole.