Roles of microRNA in prostate cancer cell metabolism

: Metabolic changes driven by the hostile tumor microenvironment surrounding cancer cells and effect of these changes on tumorigenesis and metastatic potential have been known for a long time. The usual point of interest is glucose and changes in its utilization by cancer cells, mainly in the form of the Warburg effect. However, amino acids, both intra- and extracellular, also represent an important aspect of tumour microenvironment, which can have a significant effect on cancer cell metabolism and overall development of the tumor. Namely alterations in metabolism of amino acids glutamine, sarcosine, aspartate, methionine and cysteine have been previously connected to the tumor progression and aggressivity of prostate cancer. The aim of this review is to pinpoint current gaps in our knowledge of the role of amino acids as a part of the tumor microenvironment and to show effect of various amino acids on cancer cell metabolism and metastatic potential. This review shows limitations and exceptions from the traditionally accepted model of Warburg effect in some cancer tissues, with the emphasis on prostate cancer, because the traditional definition of Warburg effect as a metabolic switch to aerobic glycolysis does not always apply. Prostatic tissue both in healthy and transformed state significantly differs in many metabolic aspects, including the metabolisms of glucose and amino acids, from metabolism of other tissues. Findings from different tissues are therefore not always interchangeable and have to be taken into account during experimentation modifying the environment of tumor tissue by amino acid supplementation or depletion, which could potentially serve as a new therapeutic approach.

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Androgens Promote Prostate Cancer Cell Growth through Induction of Autophagy

Molecular Endocrinology ◽

10.1210/me.2012-1260 ◽

2013 ◽

Vol 27 (2) ◽

pp. 280-295 ◽

Cited By ~ 45

Author(s):

Yan Shi ◽

Jenny J. Han ◽

Jayantha B. Tennakoon ◽

Fabiola F. Mehta ◽

Fatima A. Merchant ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Growth ◽

Cancer Cell ◽

Metabolic Pathways ◽

Prostate Cancer Cell ◽

Cell Metabolism ◽

Cancer Cell Growth ◽

Intracellular Lipid ◽

Intracellular Lipid Accumulation ◽

Prostatic Diseases

Abstract Androgens regulate both the physiological development of the prostate and the pathology of prostatic diseases. However, the mechanisms by which androgens exert their regulatory activities on these processes are poorly understood. In this study, we have determined that androgens regulate overall cell metabolism and cell growth, in part, by increasing autophagy in prostate cancer cells. Importantly, inhibition of autophagy using either pharmacological or molecular inhibitors significantly abrogated androgen-induced prostate cancer cell growth. Mechanistically, androgen-mediated autophagy appears to promote cell growth by augmenting intracellular lipid accumulation, an effect previously demonstrated to be necessary for prostate cancer cell growth. Further, autophagy and subsequent cell growth is potentiated, in part, by androgen-mediated increases in reactive oxygen species. These findings demonstrate a role for increased fat metabolism and autophagy in prostatic neoplasias and highlight the potential of targeting underexplored metabolic pathways for the development of novel therapeutics.

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Molecular underpinnings of RB status as a biomarker of poor outcome in advanced prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.6_suppl.189 ◽

2020 ◽

Vol 38 (6_suppl) ◽

pp. 189-189

Author(s):

Amy C. Mandigo ◽

Christopher McNair ◽

Kexin Ku ◽

Angel Pang ◽

Yi Fang Guan ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Cell ◽

Advanced Prostate Cancer ◽

Cell Metabolism ◽

Biological Significance ◽

Model Systems ◽

Poor Outcome ◽

Castration Resistant ◽

Cancer Cell Metabolism ◽

Tumor Phenotypes

189 Background: There is emergent and compelling evidence to support RB status as a biomarker in advanced prostate cancer. RB loss is strongly associated with poor progression-free, disease-specific, and overall survival in prostate cancer (PCa). Preclinical studies in PCa have revealed RB positive tumors are more responsive to CDK4/6 inhibitors. An ongoing randomized Phase IB/II study of enzalutamide with and without ribociclib in patients with metastatic castration-resistant, chemotherapy naïve PCa has become a pioneer trial to include a positive RB status as inclusion criteria in a PCa study (NCT02555189). Beyond CDK4/6 inhibitors, therapeutic agents that target tumor metabolism have been introduced in the clinic. Current data suggests that RB status may be crucial to understand and predict therapeutic response to these agents within tumors. Methods: The biological significance of RB loss was studied utilizing isogenic model systems and human tumor xenografts of castration resistant prostate cancer (CRPC) with and without RB deletion. The mechanism that drives aggressive tumor phenotypes was identified through comprehensive transcriptomic, cistromic, and metabolomic analysis. Novel functions of RB were identified and the response to clinically-relevant therapeutics was examined. Results: Exclusively in CRPC, RB loss results in significant rewiring of cancer cell metabolism. Functional investigation revealed a causative link between RB loss and antioxidant production sufficient to alter responsiveness to genomic insult and selected chemotherapeutics. Observed changes in response to therapeutic intervention were attributed to RB-dependent modulation of intracellular reactive oxygen species. Conclusions: RB loss is strongly associated with poor outcome in advanced PCa. Molecular investigation identified RB-dependent rewiring of cancer cell metabolism as a significant consequence of RB loss, sufficient to alter response in model systems to therapeutic strategies of clinical relevance. These studies significantly advance understanding of the means by which RB loss enhances lethal tumor phenotypes, and are of relevance for development of RB status as a clinically actionable biomarker.

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Memantine induces apoptosis and inhibits cell cycle progression in LNCaP prostate cancer cells

Human & Experimental Toxicology ◽

10.1177/0960327117747025 ◽

2017 ◽

Vol 37 (9) ◽

pp. 953-958 ◽

Cited By ~ 5

Author(s):

G Albayrak ◽

E Konac ◽

AU Dikmen ◽

CY Bilen

Keyword(s):

Prostate Cancer ◽

Cell Cycle ◽

Protein Expression ◽

Cancer Cell ◽

Cell Cycle Progression ◽

Cell Metabolism ◽

Glutamine Metabolism ◽

Cycle Progression ◽

Expression Levels ◽

Cancer Cell Metabolism

Deregulated cancer cell metabolism plays an important role in cancer progression. Cancer cell metabolism has been in the centre of attention in therapeutical cancer cell targeting. Repurposed chemical agents, such as metformin and aspirin, have been studied extensively as preventive and therapeutic agents. Metformin is Food and Drug administration (FDA)-approved antidiabetic drug cheaper than other chemotherapeutic agents that were shown to have anticancer effects. Memantine is an FDA-approved Alzheimer’s drug. Drug repositioning studies offer wide range of benefits, such as reduced time, cost and risk over de novo drug discovery. Therefore, we aimed to target glucose and glutamine metabolism in androgen-dependent LNCaP cells by using metformin and memantine and investigate these agents’ effects on prostate cancer cell proliferation in vitro. We evaluated the effects of metformin and memantine on the protein expression levels of genes that play significant roles in apoptosis and cell cycle progression (Casp3, Casp9, Bcl-2, Survivin, Bax, c-Myc, HIF1A, CCND1, CDK4 and GAPDH) by Western blotting. Alzheimer’s drug memantine exerted cytotoxic effects at 0.25 mM and metformin at 2.5 mM. We identified for the first time that memantine exerts antineoplastic activity (0.25 mM) by triggering Bax-dependent pathway of apoptosis. In addition to that both molecules have shown similar patterns on pro- and anti-apoptotic protein expression levels, such as Bcl-2, Casp3, Survivin and Bax. Our preclinic results indicate that memantine might be used as a new repositioned drug in cancer treatment. Beyond targeting glucose metabolism, glutamine metabolism also holds great promise for a potential treatment option.

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