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1.
Metabolic Roles of Androgen Receptor and Tip60 in Androgen-Dependent Prostate Cancer.
Tan, KN, Avery, VM, Carrasco-Pozo, C
International journal of molecular sciences. 2020;(18)
Abstract
Androgen receptor (AR)-mediated signaling is essential for the growth and differentiation of the normal prostate and is the primary target for androgen deprivation therapy in prostate cancer. Tat interactive protein 60 kDa (Tip60) is a histone acetyltransferase that is critical for AR activation. It is well known that cancer cells rewire their metabolic pathways in order to sustain aberrant proliferation. Growing evidence demonstrates that the AR and Tip60 modulate key metabolic processes to promote the survival of prostate cancer cells, in addition to their classical roles. AR activation enhances glucose metabolism, including glycolysis, tricarboxylic acid cycle and oxidative phosphorylation, as well as lipid metabolism in prostate cancer. The AR also interacts with other metabolic regulators, including calcium/calmodulin-dependent kinase kinase 2 and mammalian target of rapamycin. Several studies have revealed the roles of Tip60 in determining cell fate indirectly by modulating metabolic regulators, such as c-Myc, hypoxia inducible factor 1α (HIF-1α) and p53 in various cancer types. Furthermore, Tip60 has been shown to regulate the activity of key enzymes in gluconeogenesis and glycolysis directly through acetylation. Overall, both the AR and Tip60 are master metabolic regulators that mediate cellular energy metabolism in prostate cancer, providing a framework for the development of novel therapeutic targets in androgen-dependent prostate cancer.
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2.
Tumour metabolism and its unique properties in prostate adenocarcinoma.
Bader, DA, McGuire, SE
Nature reviews. Urology. 2020;(4):214-231
Abstract
Anabolic metabolism mediated by aberrant growth factor signalling fuels tumour growth and progression. The first biochemical descriptions of the altered metabolic nature of solid tumours were reported by Otto Warburg almost a century ago. Now, the study of tumour metabolism is being redefined by the development of new molecular tools, tumour modelling systems and precise instrumentation together with important advances in genetics, cell biology and spectroscopy. In contrast to Warburg's original hypothesis, accumulating evidence demonstrates a critical role for mitochondrial metabolism and substantial variation in the way in which different tumours metabolize nutrients to generate biomass. Furthermore, computational and experimental approaches suggest a dominant influence of the tissue-of-origin in shaping the metabolic reprogramming that enables tumour growth. For example, the unique metabolic properties of prostate adenocarcinoma are likely to stem from the distinct metabolism of the prostatic epithelium from which it emerges. Normal prostatic epithelium employs comparatively glycolytic metabolism to sustain physiological citrate secretion, whereas prostate adenocarcinoma consumes citrate to power oxidative phosphorylation and fuel lipogenesis, enabling tumour progression through metabolic reprogramming. Current data suggest that the distinct metabolic aberrations in prostate adenocarcinoma are driven by the androgen receptor, providing opportunities for functional metabolic imaging and novel therapeutic interventions that will be complementary to existing diagnostic and treatment options.
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3.
The Crosstalk between Prostate Cancer and Microbiota Inflammation: Nutraceutical Products Are Useful to Balance This Interplay?
Crocetto, F, Boccellino, M, Barone, B, Di Zazzo, E, Sciarra, A, Galasso, G, Settembre, G, Quagliuolo, L, Imbimbo, C, Boffo, S, et al
Nutrients. 2020;(9)
Abstract
The human microbiota shows pivotal roles in urologic health and disease. Emerging studies indicate that gut and urinary microbiomes can impact several urological diseases, both benignant and malignant, acting particularly on prostate inflammation and prostate cancer. Indeed, the microbiota exerts its influence on prostate cancer initiation and/or progression mechanisms through the regulation of chronic inflammation, apoptotic processes, cytokines, and hormonal production in response to different pathogenic noxae. Additionally, therapies' and drugs' responses are influenced in their efficacy and tolerability by microbiota composition. Due to this complex potential interconnection between prostate cancer and microbiota, exploration and understanding of the involved relationships is pivotal to evaluate a potential therapeutic application in clinical practice. Several natural compounds, moreover, seem to have relevant effects, directly or mediated by microbiota, on urologic health, posing the human microbiota at the crossroad between prostatic inflammation and prostate cancer development. Here, we aim to analyze the most recent evidence regarding the possible crosstalk between prostate, microbiome, and inflammation.
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4.
Adverse effects of androgen deprivation therapy in patients with prostate cancer: Focus on muscle and bone health.
Bargiota, A, Oeconomou, A, Zachos, I, Samarinas, M, L Pisters, L, Tzortzis, V
Journal of B.U.ON. : official journal of the Balkan Union of Oncology. 2020;(3):1286-1294
Abstract
Androgen deprivation therapy (ADT) is the most effective systemic treatment for prostate cancer and can be succeeded either surgically or pharmaceutically. Both approaches lead to hypogonadism with a large variety of adverse events, including obesity, metabolic syndrome, osteoporosis, sarcopenia, diabetes mellitus, cardiovascular disease, gynecomastia and sexual dysfunction. In addition, undesirable effects on muscle and bone health may have a significant impact not only on the quality of life but also on life expectancy. Currently, supervised exercise seems to be the only intervention that could prevent the adverse effects of the ADT and improve quality of life. Lifestyle modification, supplementation of calcium, vitamin D and when indicated antiosteoporotic treatments improve bone health. However, patients receiving ADT must be well informed about the potential benefits as well as the risks of the treatment.
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5.
Systemic Treatment of Bone Disease in Metastatic Urinary Malignancies.
Patel, SH, Panian, J, Bree, K, Derweesh, I, Millard, F, Randall, J, Mckay, R
European urology focus. 2020;(1):17-25
Abstract
CONTEXT Bone metastasis is a common site of metastatic disease in patients with genitourinary malignancies. Given that the presence of bone metastasis decreases survival and has a negative impact on quality of life impact, it is critical to optimize management of this patient population. OBJECTIVE To systematically review literature on the systemic treatment of bone metastasis in prostate cancer, renal cell carcinoma, urothelial carcinoma, and germ cell tumors. EVIDENCE ACQUISITION We performed a nonsystematic critical review of PubMed/Medline, clinicaltrials.gov, and the Cochrane Library from January 2001 to February 2019. Identified reports were reviewed according to the Consolidated Standards of Reporting Trials, and selected based on reporting skeletal related events and symptomatic skeletal events for patients with urologic malignancies. EVIDENCE SYNTHESIS Skeletal metastases occur frequently in genitourinary malignancies, at rates around 80% for patients with metastatic prostate cancer and 30% for patients with metastatic renal cell and urothelial carcinoma, and are uncommon in patients with germ cell tumors. Skeletal related events and symptomatic skeletal events can occur in these patients. Optimization of bone health involves dietary and lifestyle modifications, and use of osteoclast-targeted agents in select individuals. Additionally, disease-modifying agents, such as radiopharmaceutical, immunotherapy, and cMET inhibitors, which have activity in the bone, have improved outcomes for patients, including skeletal-related events and symptomatic skeletal events. CONCLUSIONS While the presence of bone metastases is associated with increased mortality and worse outcomes in patients with genitourinary malignancies, strategies have been developed to improve quality of life and survival for patients with skeletal metastases. Future studies investigating novel therapeutic options and bone supporting agents are warranted to target this patient population. PATIENT SUMMARY In this report, we reviewed the current literature and recent clinical trials involving treatment of bone metastases in urinary cancers. The use of bone-targeting agents can improve outcomes for patients, and additional lifestyle modification can optimize bone health in this population.
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6.
The diverse roles of SPOP in prostate cancer and kidney cancer.
Wang, Z, Song, Y, Ye, M, Dai, X, Zhu, X, Wei, W
Nature reviews. Urology. 2020;(6):339-350
Abstract
Multiple studies have confirmed that speckle-type pox virus and zinc finger (POZ) protein (SPOP) functions as a substrate adaptor of cullin 3-based E3 ligase and has a crucial role in various cellular processes via specific targeting of proteins for ubiquitination and subsequent proteasomal degradation. Dysregulation of SPOP-mediated proteolysis might be involved in the development and progression of human prostate and kidney cancers. In prostate cancer, SPOP seems to function as a tumour suppressor by targeting several proteins, including androgen receptor (AR), steroid receptor coactivator 3 (SRC3) and BRD4, for degradation, whereas it might function as an oncoprotein in kidney cancer, for example, by targeting phosphatase and tensin homologue (PTEN) for proteasomal degradation. In addition, nuclear SPOP targets AR for degradation and has a role as a tumour suppressor in prostate cancer; however, in kidney cancer, SPOP largely accumulates in the cytoplasm and fails to promote degradation of AR located in the nucleus, resulting in activation of AR-driven pathways and cancer progression. Owing to the context-dependent function of SPOP in human malignancies, further assessment of the molecular mechanisms involving SPOP in prostate and kidney cancers is needed to improve our understanding of its role in the development of these cancer types. Treatments that target SPOP might become therapeutic strategies in these malignancies in the future.
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7.
Drug-Drug Interactions in Prostate Cancer Treatment.
Hebenstreit, D, Pichler, R, Heidegger, I
Clinical genitourinary cancer. 2020;(2):e71-e82
Abstract
Polypharmacy is associated with an increased risk of drug-drug interactions (DDIs), which can cause serious and debilitating drug-induced adverse events. With a steadily aging population and associated increasing multimorbidity and polypharmacy, the potential for DDIs becomes considerably important. Prostate cancer (PCa) is the most common cancer in men and occurs mostly in elderly men in the Western world. Therefore, the aim of this review is to give an overview of DDIs in PCa therapy to better understand pharmacodynamic and pharm kinetic side effects as well as their interactions with other medications. Last, we explore potential future strategies, which might help to optimize treatment and reduce adverse events patients with polypharmacy and PCa.
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8.
Mobilizing serum factors and immune cells through exercise to counteract age-related changes in cancer risk.
Hwang, JH, McGovern, J, Minett, GM, Della Gatta, PA, Roberts, L, Harris, JM, Thompson, EW, Parker, TJ, Peake, JM, Neubauer, O
Exercise immunology review. 2020;:80-99
Abstract
An increasing body of evidence suggests that age-related immune changes and chronic inflammation contribute to cancer development. Recognizing that exercise has protective effects against cancer, promotes immune function, and beneficially modulates inflammation with ageing, this review outlines the current evidence indicating an emerging role for exercise immunology in preventing and treating cancer in older adults. A specific focus is on data suggesting that muscle- derived cytokines (myokines) mediate anti-cancer effects through promoting immunosurveillance against tumourigenesis or inhibiting cancer cell viability. Previous studies suggested that the exercise-induced release of myokines and other endocrine factors into the blood increases the capacity of blood serum to inhibit cancer cell growth in vitro. However, little is known about whether this effect is influenced by ageing. Prostate cancer is the second most common cancer in men. We therefore examined the effects of serum collected before and after exercise from healthy young and older men on the metabolic activity of androgen-responsive LNCaP and androgen-unresponsive PC3 prostate cancer cells. Exercise-conditioned serum collected from the young group did not alter cell metabolic activity, whereas post-exercise serum (compared with pre-exercise serum) from the older men inhibited the metabolic activity of LNCaP cancer cells. Serum levels of candidate cancer-inhibitory myokines oncostatin M and osteonectin increased in both age groups following exercise. Serum testosterone increased only in the younger men postexercise, potentially attenuating inhibitory effects of myokines on the LNCaP cell viability. The data from our study and the evidence in this review suggest that mobilizing serum factors and immune cells may be a key mechanism of how exercise counteracts cancer in the older population.
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9.
Altered expression of cytochrome P450 enzymes involved in metabolism of androgens and vitamin D in the prostate as a risk factor for prostate cancer.
Maksymchuk, OV, Kashuba, VI
Pharmacological reports : PR. 2020;(5):1161-1172
Abstract
Prostate cancer is the most common malignant disease among men. The signaling pathways, regulated by the androgen and vitamin D receptors, play a key role in prostate cancer. The intracellular level of androgens and vitamin D determines not only receptor functionality, but also the efficacy of cellular processes regulated by them (cell proliferation, apoptosis, differentiation etc.). It is known that several androgen-metabolizing P450s (CYP3A4/5/43 and CYP2B6) and P450 enzymes (CYP2R1, CYP27A1, CYP27B1, CYP24A1, CYP3A4, CYP2J2), which are necessary for vitamin D metabolism, are expressed in the prostate. It was shown that alterations in an expression pattern of the certain cytochrome P450s might lead to the development of castration-resistant cancer (CYP3A4, CYP2J2, CYP24A1), and to chemo-resistance (CYP3A4, CYP3A5, CYP2B6) and early mortality (CYP2B6, CYP27A1, CYP24A1). Moreover, steroidogenic CYPs (CYP17A1, CYP11A1) are not expressed in normal prostate tissue. Alterations in their expression levels in steroidogenic tissues are closely associated with carcinogenesis, and, most importantly, with the development of aggressive forms of prostate cancer. Hence, it is important, to study how expression of CYPs in the prostate might be regulated, to understand the mechanisms of disease development and to improve the effectiveness of therapy. Several CYPs (CYP3A43, CYP2B6, CYP27A1, CYP24A1) can be considered as prognostic and diagnostic markers of prostate cancer. To propose personalized treatment, individual differences in CYP expression should be taken into account.
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10.
Understanding the Mechanisms of Diet and Outcomes in Colon, Prostate, and Breast Cancer; Malignant Gliomas; and Cancer Patients on Immunotherapy.
Mann, S, Sidhu, M, Gowin, K
Nutrients. 2020;(8)
Abstract
Cancer patients often ask which foods would be best to consume to improve outcomes. This is a difficult question to answer as there are no case-controlled, prospective studies that control for confounding factors. Therefore, a literature review utilizing PubMed was conducted with the goal to find evidence-based support for certain diets in specific cancer patients-specifically, we reviewed data for colon cancer, prostate cancer, breast cancer, malignant gliomas, and cancer patients on immunotherapy. Improved outcomes in colon cancer and patients on immunotherapy were found with high-fiber diets. Improved outcomes in malignant gliomas were found with ketogenic diets. Improved outcomes in prostate cancer and breast cancer were found with plant-based diets. However, the data are not conclusive for breast cancer. Additionally, the increased intake of omega-3 fatty acids were also associated with better outcomes for prostate cancer. While current research, especially in humans, is minimal, the studies discussed in this review provide the groundwork for future research to further investigate the role of dietary intervention in improving cancer outcomes.