Ornithine Decarboxylase Is Sufficient for Prostate Tumorigenesis via Androgen Receptor Signaling

Shukla–Dave, Amita; Castillo-Martín, Mireia; Chen, Ming; Lobo, Jose; Gladoun, Nataliya; Collazo-Lorduy, Ana; Khan, Faisal; Ponomarev, Vladimir; Yi, Zhengzi; Zhang, Weijia; Pandolfi, Pier Paolo; Hricak, Hedvig; Cordon‐Cardo, Carlos

doi:10.1016/j.ajpath.2016.08.021

Cited by 30 publications

(27 citation statements)

References 57 publications

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“…We also observed decreased levels of myoinositol, inosine, adenosine, asparagine, aspartate, and guanosine, which have been previously reported as being depleted in metastatic PC tissue 49 , indicating that activation of OR51E2 by agonists in LNCaP cells produces metabolic signatures similar to those observed in human metastatic tissues. Agonist treatment also reduced levels of intracellular urea and spermine/spermidine, in accordance with recently reported data showing reduced spermine during malignant transformation 63 . Accordingly, we also detected decreased intracellular levels of ornithine, a precursor of polyamines.…”

Section: Metabolomic Signatures Of Lncap Cells Treated With Selected supporting

confidence: 92%

A testosterone metabolite 19-hydroxyandrostenedione induces neuroendocrine trans-differentiation of prostate cancer cells via an ectopic olfactory receptor

Abaffy

Bain

Muehlbauer

et al. 2018

Preprint

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Olfactory receptor OR51E2, also known as a Prostate Specific G-Protein Receptor, is highly expressed in prostate cancer but its function is not well understood. Through in silico and in vitro analyses, we identified 24 agonists and 1 antagonist for this receptor. We detected that agonist 19hydroxyandrostenedione, a product of the aromatase reaction, is endogenously produced upon receptor activation. We characterized the effects of receptor activation on metabolism using a prostate cancer cell line and demonstrated decreased intracellular anabolic signals and cell viability, induction of cell cycle arrest, and increased expression of neuronal markers. Furthermore, upregulation of neuron-specific enolase by agonist treatment was abolished in OR51E2-KO cells. The results of our study suggest that OR51E2 activation results in neuroendocrine trans-differentiation.These findings reveal a new role for OR51E2 and establish this G-protein coupled receptor as a novel therapeutic target in the treatment of prostate cancer. 2 Significance:Prostate cancer is the second most common cancer in men. Most deaths from prostate cancer are due to the progression of localized disease into metastatic, castration-resistant prostate cancer characterized by increased number of neuroendocrine-like cells. These neuroendocrine-like cells are non-proliferating, terminally differentiated cells. Olfactory receptor OR51E2, also known as a Prostate Specific G-Protein Receptor, is highly expressed in prostate cancer, and its expression correlates with disease progression. Here, we identify and validate novel endogenous ligands for this receptor.We show that activation of OR51E2 by newly-discovered prostate cancer-relevant agonists facilitates cellular transformation, resulting in neuroendocrine trans-differentiation, a characteristic phenotype of castrate resistant prostate cancer. Our results establish this G-protein coupled receptor as a novel and therapeutic target for castration-resistant prostate cancer. Highlights:• Discovery of novel agonists for olfactory receptor OR51E2/PSGR highly relevant to prostate cancer pathology• Activation of OR51E2 receptor by agonist N-acetyl-N-formyl-5-methoxykynurenamine (AFMK) results in release of 19-hydroxyandrostenedione (19-OH AD) from the prostate cancer cells indicating its endogenous production • Activation of OR51E2 receptor by 19-OH AD, AFMK, and propionic acid decreases anabolic and proliferative signals 3 • Activation of OR51E2 receptor by 19-OH AD and AFMK increases markers specific for neuroendocrine trans-differentiation (NEtD)• Ablation of the OR51E2 gene in prostate cancer cells treated with agonist 19-OH AD significantly reduces neuron-specific enolase INTRODUCTION G-protein coupled receptors (GPCRs) have emerged as important factors in tumor growth and metastasis 1-3 . Several GPCRs, such as the 5HT1c serotonin receptor 4 , the M1, M3, and M5 muscarinic receptors 5 , and the α1B-ADR adrenergic receptor 6 , can function as oncogenes when persistently activated. These GPCRs, which are normally...

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Section: Metabolomic Signatures Of Lncap Cells Treated With Selected supporting

confidence: 92%

A testosterone metabolite 19-hydroxyandrostenedione induces neuroendocrine trans-differentiation of prostate cancer cells via an ectopic olfactory receptor

Abaffy

Bain

Muehlbauer

et al. 2018

Preprint

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“…ODC is a focus of therapies that aim to prevent carcinogenesis because it is a transcriptional target of a proto-oncogene [ 344 , 345 , 346 ], and many studies have shown that transfection of the ODC gene results in increased intracellular polyamine levels and malignant transformation [ 347 , 348 , 349 , 350 , 351 , 352 , 353 ]. Most reports on the roles of ODC in malignant transformation have examined cells that were already at risk of tumorigenesis.…”

Section: Possible Role Of Polyamines In Inhibiting Tumorigenesismentioning

confidence: 99%

Polyamine Metabolism and Gene Methylation in Conjunction with One-Carbon Metabolism

Soda

2018

IJMS

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Recent investigations have revealed that changes in DNA methylation status play an important role in aging-associated pathologies and lifespan. The methylation of DNA is regulated by DNA methyltransferases (DNMT1, DNMT3a, and DNMT3b) in the presence of S-adenosylmethionine (SAM), which serves as a methyl group donor. Increased availability of SAM enhances DNMT activity, while its metabolites, S-adenosyl-l-homocysteine (SAH) and decarboxylated S-adenosylmethionine (dcSAM), act to inhibit DNMT activity. SAH, which is converted from SAM by adding a methyl group to cytosine residues in DNA, is an intermediate precursor of homocysteine. dcSAM, converted from SAM by the enzymatic activity of adenosylmethionine decarboxylase, provides an aminopropyl group to synthesize the polyamines spermine and spermidine. Increased homocysteine levels are a significant risk factor for the development of a wide range of conditions, including cardiovascular diseases. However, successful homocysteine-lowering treatment by vitamins (B6, B12, and folate) failed to improve these conditions. Long-term increased polyamine intake elevated blood spermine levels and inhibited aging-associated pathologies in mice and humans. Spermine reversed changes (increased dcSAM, decreased DNMT activity, aberrant DNA methylation, and proinflammatory status) induced by the inhibition of ornithine decarboxylase. The relation between polyamine metabolism, one-carbon metabolism, DNA methylation, and the biological mechanism of spermine-induced lifespan extension is discussed.

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“…In combination with other pro-cancerous events such as expression of a mutated Ras oncogene ODC promotes invasiveness of skin cancer cells [ 122 ]. Overexpression of this enzyme in normal prostate cells is sufficient for their malignant transformation [ 123 ]. In this study, a strong up-regulation of the main polyamine enzymes (ODC, spermine oxidase, spermine synthase) and a concomitant reduction of spermine was observed in high-grade prostate intraepithelial neoplasia (HGPIN) tissues as compared to normal prostate glands with the expression levels for SMOX expression being the highest.…”

Section: Biogenic Polyamines At the Crossroads Of Redox Statusmentioning

confidence: 99%

Polyamine Metabolism and Oxidative Protein Folding in the ER as ROS-Producing Systems Neglected in Virology

Smirnova

Bartosch

Zakirova

et al. 2018

IJMS

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Reactive oxygen species (ROS) are produced in various cell compartments by an array of enzymes and processes. An excess of ROS production can be hazardous for normal cell functioning, whereas at normal levels, ROS act as vital regulators of many signal transduction pathways and transcription factors. ROS production is affected by a wide range of viruses. However, to date, the impact of viral infections has been studied only in respect to selected ROS-generating enzymes. The role of several ROS-generating and -scavenging enzymes or cellular systems in viral infections has never been addressed. In this review, we focus on the roles of biogenic polyamines and oxidative protein folding in the endoplasmic reticulum (ER) and their interplay with viruses. Polyamines act as ROS scavengers, however, their catabolism is accompanied by H2O2 production. Hydrogen peroxide is also produced during oxidative protein folding, with ER oxidoreductin 1 (Ero1) being a major source of oxidative equivalents. In addition, Ero1 controls Ca2+ efflux from the ER in response to e.g., ER stress. Here, we briefly summarize the current knowledge on the physiological roles of biogenic polyamines and the role of Ero1 at the ER, and present available data on their interplay with viral infections.

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Ornithine Decarboxylase Is Sufficient for Prostate Tumorigenesis via Androgen Receptor Signaling

Cited by 30 publications

References 57 publications

A testosterone metabolite 19-hydroxyandrostenedione induces neuroendocrine trans-differentiation of prostate cancer cells via an ectopic olfactory receptor

A testosterone metabolite 19-hydroxyandrostenedione induces neuroendocrine trans-differentiation of prostate cancer cells via an ectopic olfactory receptor

Polyamine Metabolism and Gene Methylation in Conjunction with One-Carbon Metabolism

Polyamine Metabolism and Oxidative Protein Folding in the ER as ROS-Producing Systems Neglected in Virology

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