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1.
Genes Dev ; 34(7-8): 544-559, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32079653

RESUMO

Excessive reactive oxygen species (ROS) can cause oxidative stress and consequently cell injury contributing to a wide range of diseases. Addressing the critical gaps in our understanding of the adaptive molecular events downstream ROS provocation holds promise for the identification of druggable metabolic vulnerabilities. Here, we unveil a direct molecular link between the activity of two estrogen-related receptor (ERR) isoforms and the control of glutamine utilization and glutathione antioxidant production. ERRα down-regulation restricts glutamine entry into the TCA cycle, while ERRγ up-regulation promotes glutamine-driven glutathione production. Notably, we identify increased ERRγ expression/activation as a hallmark of oxidative stress triggered by mitochondrial disruption or chemotherapy. Enhanced tumor antioxidant capacity is an underlying feature of human breast cancer (BCa) patients that respond poorly to treatment. We demonstrate that pharmacological inhibition of ERRγ with the selective inverse agonist GSK5182 increases antitumor efficacy of the chemotherapeutic paclitaxel on poor outcome BCa tumor organoids. Our findings thus underscore the ERRs as novel redox sensors and effectors of a ROS defense program and highlight the potential therapeutic advantage of exploiting ERRγ inhibitors for the treatment of BCa and other diseases where oxidative stress plays a central role.


Assuntos
Neoplasias da Mama/fisiopatologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Receptores de Estrogênio/metabolismo , Transdução de Sinais/fisiologia , Animais , Antineoplásicos/farmacologia , Técnicas Biossensoriais , Neoplasias da Mama/tratamento farmacológico , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glutamina/metabolismo , Glutationa/metabolismo , Humanos , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Paclitaxel/farmacologia , Receptores de Estrogênio/genética , Rotenona/farmacologia , Tamoxifeno/análogos & derivados , Tamoxifeno/farmacologia , Receptor ERRalfa Relacionado ao Estrogênio
2.
Genes Dev ; 31(12): 1228-1242, 2017 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-28724614

RESUMO

Androgen receptor (AR) signaling reprograms cellular metabolism to support prostate cancer (PCa) growth and survival. Another key regulator of cellular metabolism is mTOR, a kinase found in diverse protein complexes and cellular localizations, including the nucleus. However, whether nuclear mTOR plays a role in PCa progression and participates in direct transcriptional cross-talk with the AR is unknown. Here, via the intersection of gene expression, genomic, and metabolic studies, we reveal the existence of a nuclear mTOR-AR transcriptional axis integral to the metabolic rewiring of PCa cells. Androgens reprogram mTOR-chromatin associations in an AR-dependent manner in which activation of mTOR-dependent metabolic gene networks is essential for androgen-induced aerobic glycolysis and mitochondrial respiration. In models of castration-resistant PCa cells, mTOR was capable of transcriptionally regulating metabolic gene programs in the absence of androgens, highlighting a potential novel castration resistance mechanism to sustain cell metabolism even without a functional AR. Remarkably, we demonstrate that increased mTOR nuclear localization is indicative of poor prognosis in patients, with the highest levels detected in castration-resistant PCa tumors and metastases. Identification of a functional mTOR targeted multigene signature robustly discriminates between normal prostate tissues, primary tumors, and hormone refractory metastatic samples but is also predictive of cancer recurrence. This study thus underscores a paradigm shift from AR to nuclear mTOR as being the master transcriptional regulator of metabolism in PCa.


Assuntos
Regulação Neoplásica da Expressão Gênica/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/fisiopatologia , Receptores Androgênicos/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Androgênios/metabolismo , Núcleo Celular/metabolismo , DNA/metabolismo , Progressão da Doença , Humanos , Masculino , Ligação Proteica , Serina-Treonina Quinases TOR/genética , Transcrição Gênica
3.
Genes Dev ; 30(9): 1034-46, 2016 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-27151976

RESUMO

The tumor suppressor folliculin (FLCN) forms a repressor complex with AMP-activated protein kinase (AMPK). Given that AMPK is a master regulator of cellular energy homeostasis, we generated an adipose-specific Flcn (Adipoq-FLCN) knockout mouse model to investigate the role of FLCN in energy metabolism. We show that loss of FLCN results in a complete metabolic reprogramming of adipose tissues, resulting in enhanced oxidative metabolism. Adipoq-FLCN knockout mice exhibit increased energy expenditure and are protected from high-fat diet (HFD)-induced obesity. Importantly, FLCN ablation leads to chronic hyperactivation of AMPK, which in turns induces and activates two key transcriptional regulators of cellular metabolism, proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) and estrogen-related receptor α (ERRα). Together, the AMPK/PGC-1α/ERRα molecular axis positively modulates the expression of metabolic genes to promote mitochondrial biogenesis and activity. In addition, mitochondrial uncoupling proteins as well as other markers of brown fat are up-regulated in both white and brown FLCN-null adipose tissues, underlying the increased resistance of Adipoq-FLCN knockout mice to cold exposure. These findings identify a key role of FLCN as a negative regulator of mitochondrial function and identify a novel molecular pathway involved in the browning of white adipocytes and the activity of brown fat.


Assuntos
Tecido Adiposo Bege/metabolismo , Metabolismo Energético/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Proteínas Proto-Oncogênicas/genética , Receptores de Estrogênio/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Quinases Ativadas por AMP/genética , Animais , Temperatura Baixa , Ativação Enzimática/genética , Regulação da Expressão Gênica/genética , Camundongos , Camundongos Knockout , Obesidade/enzimologia , Obesidade/genética , Oxirredução , Proteínas Proto-Oncogênicas/metabolismo , Receptores de Estrogênio/genética , Transdução de Sinais , Proteínas Supressoras de Tumor/metabolismo , Receptor ERRalfa Relacionado ao Estrogênio
4.
Environ Res ; 204(Pt B): 112085, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34562481

RESUMO

Because of their historical mode of action, endocrine-disrupting chemicals (EDCs) are associated with sex-steroid receptors, namely the two estrogen receptors (ERα and ERß) and the androgen receptor (AR). Broadly, EDCs can modulate sex-steroid receptor functions. They can also indirectly impact the androgen and estrogen pathways by influencing steroidogenesis, expression of AR or ERs, and their respective activity as transcription factors. Additionally, many of these chemicals have multiple cellular targets other than sex-steroid receptors, which results in a myriad of potential effects in humans. The current article reviews the association between prostate cancer and the endocrine-disrupting functions of four prominent EDC families: bisphenols, phthalates, phytoestrogens, and mycoestrogens. Results from both in vitro and in vivo models are included and discussed to better assess the molecular mechanisms by which EDCs can modify prostate biology. To overcome the heterogeneity of results published, we established common guidelines to properly study EDCs in the context of endocrine diseases. Firstly, the expression of sex-steroid receptors in the models used must be determined before testing. Then, in parallel to EDCs, pharmacological compounds acting as positive (agonists) and negative controls (antagonists) have to be employed. Finally, EDCs need to be used in a precise range of concentrations to modulate sex-steroid receptors and avoid off-target effects. By adequately integrating molecular endocrinology aspects in EDC studies and identifying their underlying molecular mechanisms, we will truly understand their impact on prostate cancer and distinguish those that favor the progression of the disease from those that slow down tumor development.


Assuntos
Disruptores Endócrinos , Neoplasias da Próstata , Disruptores Endócrinos/toxicidade , Receptor beta de Estrogênio , Humanos , Masculino , Próstata , Neoplasias da Próstata/induzido quimicamente , Receptores de Estrogênio
5.
Br J Cancer ; 122(7): 1068-1076, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32047296

RESUMO

BACKGROUND: Perturbation of the major UGT2B17-dependent androgen catabolism pathway has the potential to affect prostate cancer (PCa) progression. The objective was to evaluate UGT2B17 protein expression in primary tumours in relation to hormone levels, disease characteristics and cancer evolution. METHODS: We conducted an analysis of a high-density prostate tumour tissue microarray consisting of 239 localised PCa cases treated by radical prostatectomy (RP). Cox proportional hazard ratio analysis was used to evaluate biochemical recurrence (BCR), and a linear regression model evaluated variations in circulating hormone levels measured by mass spectrometry. The transcriptome of UGT2B17 in PCa was established by using RNA-sequencing data. RESULTS: UGT2B17 expression in primary tumours was associated with node-positive disease at RP and linked to circulating levels of 3α-diol-17 glucuronide, a major circulating DHT metabolite produced by the UGT2B17 pathway. UGT2B17 was an independent prognostic factor linked to BCR after RP, and its overexpression was associated with development of metastasis. Finally, we demonstrated that distinctive alternative promoters dictate UGT2B17-dependent androgen catabolism in localised and metastatic PCa. CONCLUSIONS: The androgen-inactivating gene UGT2B17 is controlled by overlooked regulatory regions in PCa. UGT2B17 expression in primary tumours influences the steroidome, and is associated with relevant clinical outcomes, such as BCR and metastasis.


Assuntos
Androgênios/metabolismo , Glucuronosiltransferase/metabolismo , Antígenos de Histocompatibilidade Menor/metabolismo , Neoplasias da Próstata/genética , Adulto , Idoso , Progressão da Doença , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/patologia
6.
World J Urol ; 35(2): 293-298, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27277477

RESUMO

OBJECTIVES: A few preliminary studies have suggested a link between some genetics variants and benign prostatic hyperplasia (BPH). Our goal was to study the link between a set of single nucleotide polymorphisms (SNPs) implicated in the steroid pathway and accurate measurement of prostate volume in a cohort of men who underwent radical prostatectomy. METHODS: Clinical and pathological data including prostate weight were obtained from 611 Caucasian patients with small volume, localized prostate cancer treated by radical prostatectomy. Patients were genotyped for 90 SNPs located inside or nearby genes implicated in the steroid pathway (Sequenom iPLEX). Correlation between prostate weight and genotypes from each SNP was studied by analysis of covariance, adjusted on age and tumor stage. A Bonferroni correction was applied, and the SNPs implicated were then incorporated in a multivariable model. RESULTS AND LIMITATIONS: Seven SNPs located in or nearby genes implicated in steroid hormone metabolism were significantly associated with prostate volume: HSD17B2 (rs1119933), ESR2 (rs8006145), SULT2B1 (rs279451), NQO1 (rs2917670), ESR1 (rs1569788), GSTP1 (rs1138272), and CYP19A1 (rs17523880). Significant association was maintained after multivariate analysis for four SNPs, indicating their independent association with prostate volume. The power of the association of each SNP with prostate volume was comparable to the effect of age. The strongest associations were found with variants in ESR1, ESR2, HSD17B2, and CYP19A1 genes, indicating a potential role of the estrogen signaling pathway in genesis of BPH. CONCLUSIONS: Our results are in favor of an implication of estrogen biotransformation and signaling pathways in the pathophysiology of BPH.


Assuntos
Polimorfismo de Nucleotídeo Único , Próstata/patologia , Hiperplasia Prostática/genética , Hiperplasia Prostática/patologia , Transdução de Sinais/genética , Adulto , Idoso , Hormônios Esteroides Gonadais/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Prostatectomia , Hiperplasia Prostática/cirurgia
7.
Acta Pharmacol Sin ; 36(1): 51-61, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25500872

RESUMO

The identification of the estrogen-related receptors (ERRs) as the first orphan nuclear receptors ignited a new era in molecular endocrinology, which led to the discovery of new ligand-dependent response systems. Although ERR subfamily members have yet to be associated with a natural ligand, the characterization of these orphan receptors has demonstrated that they occupy a strategic node in the transcriptional control of cellular energy metabolism. In particular, ERRs are required for the response to various environmental challenges that require high energy levels by the organism. As central regulators of energy homeostasis, ERRs may also be implicated in the etiology of metabolic disorders, such as type 2 diabetes and metabolic syndrome. Here, we review the recent evidence that further highlights the role of ERRs in metabolic control, particularly in liver and skeletal muscle, and their likely involvement in metabolic diseases. Consequently, we also explore the promises and pitfalls of ERRs as potential therapeutic targets.


Assuntos
Doenças Metabólicas/metabolismo , Receptores de Estrogênio/metabolismo , Animais , Homeostase/fisiologia , Humanos , Ligantes , Receptor ERRalfa Relacionado ao Estrogênio
8.
Data Brief ; 57: 110870, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-39290430

RESUMO

Sex hormones are necessary for the development and functions of the normal prostate as well as for the initiation and progression of prostate tumors. Indeed, androgens and estrogens can activate their respective nuclear receptors to modulate the expression of multiple genes and pathways in prostate cells. Nevertheless, the androgen and estrogen responses in the normal prostate, and the transcriptomic changes occurring after carcinogenesis, remain poorly understood. Here, wildtype mice and transgenic mice that spontaneously develop prostate cancer (C57BL/6J PB-Cre4+/-;Pten fl/fl) were castrated to ensure hormone deprivation. After three days, animals received injections of testosterone and/or estradiol. After one day, the prostates were harvested, and RNA was purified for sequencing. Sequencing data were then analyzed to study transcriptional modulations following hormonal exposures in normal and tumoral murine prostates. New analyses can be carried out with specific fold-change thresholds for gene expression, or with different pair-wise combinations between conditions (treatments and/or mouse models). Together, the data generated herein are a useful tool to study hormonal transcriptional responses in prostate and prostate cancer biology.

9.
STAR Protoc ; 5(3): 103200, 2024 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-39028619

RESUMO

Patient-derived organoids (PDOs) are now used to study many diseases, including prostate cancer. Here, we present a protocol for the transduction of human epithelial prostate cells and PDOs. We describe the steps for producing lentiviruses and transducing PDOs with high efficiency to obtain either overexpression or knockdown of specific genes. More generally, this protocol represents an efficient lentiviral transduction technique to study cell biology using various organoid models.


Assuntos
Células Epiteliais , Lentivirus , Organoides , Próstata , Humanos , Organoides/citologia , Organoides/metabolismo , Masculino , Próstata/citologia , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Lentivirus/genética , Transdução Genética/métodos , Neoplasias da Próstata/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo
10.
J Steroid Biochem Mol Biol ; 243: 106588, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39025336

RESUMO

The prevailing biomarker employed for prostate cancer (PCa) screening and diagnosis is the prostate-specific antigen (PSA). Despite excellent sensitivity, PSA lacks specificity, leading to false positives, unnecessary biopsies and overdiagnosis. Consequently, PSA is increasingly less used by clinicians, thus underscoring the imperative for the identification of new biomarkers. An emerging biomarker in this context is citrate, a molecule secreted by the normal prostate, which has been shown to be inversely correlated with PCa. Here, we discuss about PSA and its usage for PCa diagnosis, its lack of specificity, and the various conditions that can affect its levels. We then provide our vision about what we think would be a valuable addition to our PCa diagnosis toolkit, citrate. We describe the unique citrate metabolic program in the prostate and how this profile is reprogrammed during carcinogenesis. Finally, we summarize the evidence that supports the usage of citrate as a biomarker for PCa diagnosis, as it can be measured in various patient samples and be analyzed by several methods. The unique relationship between citrate and PCa, combined with the stability of citrate levels in other prostate-related conditions and the simplicity of its detection, further accentuates its potential as a biomarker.


Assuntos
Biomarcadores Tumorais , Ácido Cítrico , Antígeno Prostático Específico , Neoplasias da Próstata , Humanos , Masculino , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/sangue , Neoplasias da Próstata/metabolismo , Antígeno Prostático Específico/sangue , Biomarcadores Tumorais/sangue , Ácido Cítrico/metabolismo , Próstata/patologia , Próstata/metabolismo
11.
J Clin Invest ; 134(11)2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38625747

RESUMO

Just like the androgen receptor (AR), the estrogen receptor α (ERα) is expressed in the prostate and is thought to influence prostate cancer (PCa) biology. Yet the incomplete understanding of ERα functions in PCa hinders our ability to fully comprehend its clinical relevance and restricts the repurposing of estrogen-targeted therapies for the treatment of this disease. Using 2 human PCa tissue microarray cohorts, we first demonstrate that nuclear ERα expression was heterogeneous among patients, being detected in only half of the tumors. Positive nuclear ERα levels were correlated with disease recurrence, progression to metastatic PCa, and patient survival. Using in vitro and in vivo models of the normal prostate and PCa, bulk and single-cell RNA-Seq analyses revealed that estrogens partially mimicked the androgen transcriptional response and activated specific biological pathways linked to proliferation and metabolism. Bioenergetic flux assays and metabolomics confirmed the regulation of cancer metabolism by estrogens, supporting proliferation. Using cancer cell lines and patient-derived organoids, selective estrogen receptor modulators, a pure anti-estrogen, and genetic approaches impaired cancer cell proliferation and growth in an ERα-dependent manner. Overall, our study revealed that, when expressed, ERα functionally reprogrammed PCa metabolism, was associated with disease progression, and could be targeted for therapeutic purposes.


Assuntos
Proliferação de Células , Progressão da Doença , Receptor alfa de Estrogênio , Estrogênios , Neoplasias da Próstata , Transdução de Sinais , Humanos , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Neoplasias da Próstata/genética , Masculino , Receptor alfa de Estrogênio/metabolismo , Receptor alfa de Estrogênio/genética , Estrogênios/metabolismo , Animais , Camundongos , Linhagem Celular Tumoral , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/genética
12.
Sci Adv ; 10(22): eadk9681, 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38820148

RESUMO

In response to energy and nutrient shortage, the liver triggers several catabolic processes to promote survival. Despite recent progress, the precise molecular mechanisms regulating the hepatic adaptation to fasting remain incompletely characterized. Here, we report the identification of hydroxysteroid dehydrogenase-like 2 (HSDL2) as a mitochondrial protein highly induced by fasting. We show that the activation of PGC1α-PPARα and the inhibition of the PI3K-mTORC1 axis stimulate HSDL2 expression in hepatocytes. We found that HSDL2 depletion decreases cholesterol conversion to bile acids (BAs) and impairs FXR activity. HSDL2 knockdown also reduces mitochondrial respiration, fatty acid oxidation, and TCA cycle activity. Bioinformatics analyses revealed that hepatic Hsdl2 expression positively associates with the postprandial excursion of various BA species in mice. We show that liver-specific HSDL2 depletion affects BA metabolism and decreases circulating cholesterol levels upon refeeding. Overall, our report identifies HSDL2 as a fasting-induced mitochondrial protein that links nutritional signals to BAs and cholesterol homeostasis.


Assuntos
Ácidos e Sais Biliares , Colesterol , Hidroxiesteroide Desidrogenases , Animais , Humanos , Camundongos , Ácidos e Sais Biliares/metabolismo , Colesterol/metabolismo , Jejum/metabolismo , Hepatócitos/metabolismo , Homeostase , Fígado/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Mitocôndrias/metabolismo , Transdução de Sinais , Hidroxiesteroide Desidrogenases/genética , Hidroxiesteroide Desidrogenases/metabolismo
13.
Cancers (Basel) ; 15(11)2023 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-37296995

RESUMO

The aminosteroid derivative RM-581 blocks with high potency the growth of androgen-dependent (AR+) prostate cancer VCaP, 22Rv1, and LAPC-4 cells. Notably, RM-581 demonstrated superior antiproliferative activity in LAPC-4 cells compared to enzalutamide and abiraterone, two drugs that exhibited a synergistic effect in combination with RM-581. These findings suggest that RM-581 may have an action that is not directly associated with the hormonal pathway of androgens. Furthermore, RM-581 completely blocks tumor growth in LAPC-4 xenografts when given orally at 3, 10, and 30 mg/kg in non-castrated (intact) nude mice. During this study, an accumulation of RM-581 was observed in tumors compared to plasma (3.3-10 folds). Additionally, the level of fatty acids (FA) increased in the tumors and livers of mice treated with RM-581 but not in plasma. The increase was greater in unsaturated FA (21-28%) than in saturated FA (7-11%). The most affected FA were saturated palmitic acid (+16%), monounsaturated oleic acid (+34%), and di-unsaturated linoleic acid (+56%), i.e., the 3 most abundant FA, with a total of 55% of the 56 FA measured. For cholesterol levels, there was no significant difference in the tumor, liver, or plasma of mice treated or not with RM-581. Another important result was the innocuity of RM-581 in mice during a 28-day xenograft experiment and a 7-week dose-escalation study, suggesting a favorable safety window for this new promising drug candidate when given orally.

14.
Environ Int ; 179: 108132, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37657410

RESUMO

Due to its sensitivity to hormonal signaling, the mammary gland is often referred to as a sentinel organ for the study of endocrine-disrupting chemicals (EDCs), environmental pollutants that can interfere with the estrogen signaling pathway and induce mammary developmental defects. If and how EDCs impact mammary epithelial cell metabolism has not yet been documented. Herein, to study how estrogens and EDCs modulate mammary gland metabolism, we performed bioenergetic flux analyses using mouse mammary epithelial organoids compared to cells grown in monolayer culture. Several EDCs were tested, including bisphenol A (BPA), its close derivative BPS, a new BPA replacement copolyester called TritanTM, and the herbicide glyphosate. We report that estrogens reprogrammed mammary epithelial cell metabolism differently when grown in two- and three-dimensional models. Specific EDCs were also demonstrated to alter bioenergetic fluxes, thus identifying a new potential adverse effect of these molecules. Notably, organoids were more sensitive to low EDC concentrations, highlighting them as a key model for screening the impact of various environmental pollutants. Mechanistically, transcriptomic analyses revealed that EDCs interfered with the regulation of estrogen target genes and the expression of metabolic genes in organoids. Furthermore, co-treatment with the anti-estrogen fulvestrant blocked these metabolic impacts of EDCs, suggesting that, at least partially, they act through modulation of the estrogen receptor activity. Finally, we demonstrate that mammary organoids can be used for long-term studies on EDC exposure to study alterations in organogenesis/morphogenesis and that past pregnancies can modulate the sensitivity of mammary epithelial organoids to specific EDCs. Overall, this study demonstrates that estrogens and EDCs modulate mammary epithelial cell metabolism in monolayer and organoid cultures. A better understanding of the metabolic impacts of EDCs will allow a better appreciation of their adverse effects on mammary gland development and function.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Disruptores Endócrinos , Poluentes Ambientais , Feminino , Gravidez , Animais , Camundongos , Células Epiteliais , Transdução de Sinais , Disruptores Endócrinos/toxicidade , Estrogênios/toxicidade , Metabolismo Energético
15.
Nat Rev Urol ; 20(8): 480-493, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-36788359

RESUMO

Prostate cancer is well known to be dependent on the androgen receptor (AR) for growth and survival. Thus, AR is the main pharmacological target to treat this disease. However, after an initially positive response to AR-targeting therapies, prostate cancer will eventually evolve to castration-resistant prostate cancer, which is often lethal. Tumour growth was initially thought to become androgen-independent following treatments; however, results from molecular studies have shown that most resistance mechanisms involve the reactivation of AR. Consequently, tumour cells become resistant to castration - the blockade of testicular androgens - and not independent of AR per se. However, confusion still remains on how to properly define preclinical models of prostate cancer, including cell lines. Most cell lines were isolated from patients for cell culture after evolution of the tumour to castration-resistant prostate cancer, but not all of these cell lines are described as castration resistant. Moreover, castration refers to the blockade of testosterone production by the testes; thus, even the concept of "castration" in vitro is questionable. To ensure maximal transfer of knowledge from scientific research to the clinic, understanding the limitations and advantages of preclinical models, as well as how these models recapitulate cancer cell androgen dependency and can be used to study castration resistance mechanisms, is essential.


Assuntos
Androgênios , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Androgênios/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Androgênicos/metabolismo , Testosterona , Orquiectomia , Linhagem Celular Tumoral
16.
Metabolites ; 13(11)2023 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-37999253

RESUMO

Aging is not a disease; it is a natural evolution of human physiology. Medical advances have extended our life expectancy, but chronic diseases and geriatric syndrome continue to affect the increasingly aging population. Yet modern medicine perpetuates an approach based on treatment rather than prevention and education. In order to help solve this ever-growing problem, a new discipline has emerged: lifestyle medicine. Nutrition, physical activity, stress management, restorative sleep, social connection, and avoidance of risky substances are the pillars on which lifestyle medicine is founded. The aim of this discipline is to increase healthspan and reduce the duration of morbidity by making changes to our lifestyle. In this review, we propose the use of klotho protein as a novel biomarker for lifestyle medicine in order to quantify and monitor the health status of individuals, as no integrative tool currently exists.

17.
Cancers (Basel) ; 15(8)2023 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-37190179

RESUMO

A human transcriptome array on ERα-positive breast cancer continuum of risk identified Secreted Frizzled-Related Protein 1 (SFRP1) as decreased during breast cancer progression. In addition, SFRP1 was inversely associated with breast tissue age-related lobular involution, and differentially regulated in women with regard to their parity status and the presence of microcalcifications. The causal role of SFRP1 in breast carcinogenesis remains, nevertheless, not well understood. In this study, we characterized mammary epithelial cells from both nulliparous and multiparous mice in organoid culture ex vivo, in the presence of estradiol (E2) and/or hydroxyapatite microcalcifications (HA). Furthermore, we have modulated SFRP1 expression in breast cancer cell lines, including the MCF10A series, and investigated their tumoral properties. We observed that organoids obtained from multiparous mice were resistant to E2 treatment, while organoids obtained from nulliparous mice developed the luminal phenotype associated with a lower ratio between Sfrp1 and Esr1 expression. The decrease in SFRP1 expression in MCF10A and MCF10AT1 cell lines increased their tumorigenic properties in vitro. On the other hand, the overexpression of SFRP1 in MCF10DCIS, MCF10CA1a, and MCF7 reduced their aggressiveness. Our results support the hypothesis that a lack of SFRP1 could have a causal role in early breast carcinogenesis.

18.
Mol Oncol ; 17(10): 2109-2125, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37086156

RESUMO

The androgen receptor (AR) is an established orchestrator of cell metabolism in prostate cancer (PCa), notably by inducing an oxidative mitochondrial program. Intriguingly, AR regulates cytoplasmic isocitrate dehydrogenase 1 (IDH1), but not its mitochondrial counterparts IDH2 and IDH3. Here, we aimed to understand the functional role of IDH1 in PCa. Mouse models, in vitro human PCa cell lines, and human patient-derived organoids (PDOs) were used to study the expression and activity of IDH enzymes in the normal prostate and PCa. Genetic and pharmacological inhibition of IDH1 was then combined with extracellular flux analyses and gas chromatography-mass spectrometry for metabolomic analyses and cancer cell proliferation in vitro and in vivo. In PCa cells, more than 90% of the total IDH activity is mediated through IDH1 rather than its mitochondrial counterparts. This profile seems to originate from the specialized prostate metabolic program, as observed using mouse prostate and PDOs. Pharmacological and genetic inhibition of IDH1 impaired mitochondrial respiration, suggesting that this cytoplasmic enzyme contributes to the mitochondrial tricarboxylic acid cycle (TCA) in PCa. Mass spectrometry-based metabolomics confirmed this hypothesis, showing that inhibition of IDH1 impairs carbon flux into the TCA cycle. Consequently, inhibition of IDH1 decreased PCa cell proliferation in vitro and in vivo. These results demonstrate that PCa cells have a hybrid cytoplasmic-mitochondrial TCA cycle that depends on IDH1. This metabolic enzyme represents a metabolic vulnerability of PCa cells and a potential new therapeutic target.


Assuntos
Ciclo do Ácido Cítrico , Neoplasias da Próstata , Masculino , Camundongos , Animais , Humanos , Isocitrato Desidrogenase/genética , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Mitocôndrias/metabolismo , Citosol/metabolismo
19.
Res Sq ; 2023 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-38196574

RESUMO

Background: Myocarditis is an inflammation of the heart muscle most often caused by an immune response to viral infections. Sex differences in the immune response during myocarditis have been well described but upstream mechanisms in the heart that might influence sex differences in disease are not completely understood. Methods: Male and female BALB/c wild type mice received an intraperitoneal injection of heart-passaged coxsackievirus B3 (CVB3) or vehicle control. Bulk-tissue RNA-sequencing was conducted to better understand sex differences in CVB3 myocarditis. We performed enrichment analysis to understand sex differences in the transcriptional landscape of myocarditis and identify candidate transcription factors that might drive sex differences in myocarditis. Results: The hearts of male and female mice with myocarditis were significantly enriched for pathways related to an innate and adaptive immune response compared to uninfected controls. When comparing females to males with myocarditis, males were enriched for inflammatory pathways and gene changes that suggested worse mitochondrial transcriptional support (e.g., mitochondrial electron transport genes). In contrast, females were enriched for pathways related to mitochondrial respiration and bioenergetics, which were confirmed by higher transcript levels of master regulators of mitochondrial function including peroxisome proliferator-activated receptor gamma coactivator 1 (PGC1α), nuclear respiratory factor 1 (NRF1) and estrogen-related receptor alpha (ERRα). TRANSFAC analysis identified ERRa as a transcription factor that may mediate sex differences in mitochondrial function during myocarditis. Conclusions: Master regulators of mitochondrial function were elevated in females with myocarditis compared to males and may promote sex differences in mitochondrial respiratory transcript expression during viral myocarditis resulting in less severe myocarditis in females following viral infection.

20.
Cancer Lett ; 553: 215994, 2023 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-36343786

RESUMO

The androgen inactivating UGT2B28 pathway emerges as a predictor of progression in prostate cancer (PCa). However, the clinical significance of UGT2B28 tumoral expression and its contribution to PCa progression remain unclear. Using the Canadian Prostate Cancer Biomarker Network biobank (CPCBN; n = 1512), we analyzed UGT2B28 tumor expression in relation to clinical outcomes in men with localized PCa. UGT2B28 was overexpressed in tumors compared to paired normal adjacent prostatic tissue and was associated with inferior outcomes. Functional analyses indicated that UGT2B28 promoted cell proliferation, and its expression was regulated by the androgen receptor (AR)/ARv7. Mechanistically, UGT2B28 was shown to be a protein partner of the endocytic adaptor protein huntingtin-interacting protein 1 (HIP1), increasing its stability and priming AR/epidermal growth factor receptor (EGFR) pathways, leading to ERK1/2 activation triggering cell proliferation and epithelial-to-mesenchymal transition (EMT). HIP1 knockdown in UGT2B28 positive cells, and dual pharmacological targeting of AR and EGFR pathways, abolished cell proliferative advantages conferred by UGT2B28. In conclusion, UGT2B28 is a prognosticator of progression in localized PCa, regulates both AR and EGFR oncogenic signaling pathways via HIP1, and therefore can be therapeutically targeted by using combination of existing AR/EGFR inhibitors.


Assuntos
Neoplasias da Próstata , Receptores Androgênicos , Masculino , Humanos , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Próstata/patologia , Receptores ErbB/metabolismo , Linhagem Celular Tumoral , Canadá , Neoplasias da Próstata/patologia , Proteínas de Ligação a DNA/genética
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