Androgens enhance the glycolytic metabolism and lactate export in prostate cancer cells by modulating the expression of GLUT1, GLUT3, PFK, LDH and MCT4 genes

Vaz, Cátia V.; Marques, Ricardo; Alves, Marco G.; Oliveira, Pedro F.; Cavaco, José E.; Maia, Cláudio J.; Socorro, Sílvia

doi:10.1007/s00432-015-1992-4

Cited by 53 publications

(43 citation statements)

References 47 publications

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“…Therefore, our findings suggest that these processes may play a critical role in mediating the deleterious effects of androgens in the physiology of the renal cells. In this sense, DHT has been shown to alter glycolytic metabolism and impair mitochondrial function in other cell types (66,67). As recently reported by Wang et al, pancreatic islets from DHT-treated rats showed significant changes in the levels of several key genes involved in mitochondrial biogenesis, mitochondrial oxygen consumption rate, and ATP production.…”

Section: Figsupporting

confidence: 55%

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Stable Isotope Labeling with Amino Acids (SILAC)-Based Proteomics of Primary Human Kidney Cells Reveals a Novel Link between Male Sex Hormones and Impaired Energy Metabolism in Diabetic Kidney Disease

Clotet

Soler

Riera

et al. 2017

Molecular & Cellular Proteomics

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Male sex predisposes to many kidney diseases. Considering that androgens exert deleterious effects in a variety of cell types within the kidney, we hypothesized that dihydrotestosterone (DHT) would alter the biology of the renal tubular cell by inducing changes in the proteome. We employed stable isotope labeling with amino acids (SILAC) in an indirect spike-in fashion to accurately quantify the proteome in DHT-and 17␤-estradiol (EST)-treated human proximal tubular epithelial cells (PTEC). Of the 5043 quantified proteins, 76 were differentially regulated. Biological processes related to energy metabolism were significantly enriched among DHT-regulated proteins. SILAC ratios of 3 candidates representing glycolysis, Nacetylglucosamine metabolism and fatty acid ␤-oxidation, namely glucose-6-phosphate isomerase (GPI), glucosamine-6-phosphate-N-acetyltransferase 1 (GNPNAT1), and mitochondrial trifunctional protein subunit alpha (HADHA), were verified in vitro. In vivo, renal GPI and HADHA protein expression was significantly increased in males. Furthermore, male sex was associated with significantly higher GPI, GNPNAT1, and HADHA kidney protein expression in two different murine models of diabetes. Enrichment analysis revealed a link between our DHTregulated proteins and oxidative stress within the diabetic kidney. This finding was validated in vivo, as we observed increased oxidative stress levels in control and diabetic male kidneys, compared with females. This in depth quantitative proteomics study of human primary PTEC response to sex hormone administration suggests that male sex hormone stimulation results in perturbed energy metabolism in kidney cells, and that this perturbation results in increased oxidative stress in the renal cortex. Chronic Kidney Disease (CKD)1 often results in irreversible deterioration of renal function that can progress to renal failure (1). Sex plays a relevant role in the progression and severity of many kidney diseases (2). At a clinical level, it is From the ‡Department

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Section: Figsupporting

confidence: 55%

“…The authors also demonstrated that androgens can directly impair beta cell function by inducing mitochondrial dysfunction in vitro in an AR-dependent manner (66). In a different context, DHT enhanced glucose consumption and lactate export in prostate cancer cells (67).…”

Section: Figmentioning

confidence: 96%

Stable Isotope Labeling with Amino Acids (SILAC)-Based Proteomics of Primary Human Kidney Cells Reveals a Novel Link between Male Sex Hormones and Impaired Energy Metabolism in Diabetic Kidney Disease

Clotet

Soler

Riera

et al. 2017

Molecular & Cellular Proteomics

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show abstract

“…Like MYC, AR regulates expression of many genes involved in glutamine and glucose metabolism. Androgen signaling stimulates glucose consumption as well as production and export of lactate by upregulating the expression of GLUT1/GLUT3, phosphofructokinase 1 (PFK 1), monocarboxylate transporter 4 (MCT4), and calmodulin-dependent kinase kinase 2 (CAMKK2) genes [76,77]. CAMKK2 is highly upregulated in PCa, and CAMKK2-dependent activation of AMP-regulated kinase (AMPK) results in an increased PFK1 activity and promotes glucose uptake and lactate production [78].…”

Section: Androgen Signaling and Pca Metabolismmentioning

confidence: 99%

Concise Review: Prostate Cancer Stem Cells: Current Understanding

et al. 2018

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Prostate cancer (PCa) is heterogeneous, harboring phenotypically diverse cancer cell types. PCa cell heterogeneity is caused by genomic instability that leads to the clonal competition and evolution of the cancer genome and by epigenetic mechanisms that result in subclonal cellular differentiation. The process of tumor cell differentiation is initiated from a population of prostate cancer stem cells (PCSCs) that possess many phenotypic and functional properties of normal stem cells. Since the initial reports on PCSCs in 2005, there has been much effort to elucidate their biological properties, including unique metabolic characteristics. In this Review, we discuss the current methods for PCSC enrichment and analysis, the hallmarks of PCSC metabolism, and the role of PCSCs in tumor progression. Stem Cells 2018;36:1457-1474.

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“…70 However, these transporters, particularly GLUT1, are downregulated by DHT in non-tumor Sertoli cells. 71 Thus, hormonal regulation of GLUT1/3 seems to be tissuedependent.…”

Section: Glut Transporters As Clinical Targets In Pcamentioning

confidence: 99%

The dark side of glucose transporters in prostate cancer: Are they a new feature to characterize carcinomas?

González-Menéndez

Hevia

Mayo

et al. 2017

Intl Journal of Cancer

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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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Androgens enhance the glycolytic metabolism and lactate export in prostate cancer cells by modulating the expression of GLUT1, GLUT3, PFK, LDH and MCT4 genes

Cited by 53 publications

References 47 publications

Stable Isotope Labeling with Amino Acids (SILAC)-Based Proteomics of Primary Human Kidney Cells Reveals a Novel Link between Male Sex Hormones and Impaired Energy Metabolism in Diabetic Kidney Disease

Stable Isotope Labeling with Amino Acids (SILAC)-Based Proteomics of Primary Human Kidney Cells Reveals a Novel Link between Male Sex Hormones and Impaired Energy Metabolism in Diabetic Kidney Disease

Concise Review: Prostate Cancer Stem Cells: Current Understanding

The dark side of glucose transporters in prostate cancer: Are they a new feature to characterize carcinomas?

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