bims-polyam 2024-12-29 papers

Issue of 2024–12–29
three papers selected by
Sebastian J. Hofer, University of Graz

J Cell Immunol. 2024 ;6(5): 196-208

Polyamines: Key Players in Immunometabolism and Immune Regulation.

Polyamines are small organic molecules ubiquitously present in all living organisms and function as crucial regulators of biological processes ranging from fundamental cellular metabolism to immune regulation. Dysregulation of polyamine metabolism has been implicated in numerous diseases, including neurodegenerative disorders, inflammatory conditions, autoimmune diseases, and cancer. This review provides an overview of pathophysiology of these conditions, highlighting polyamines' role in immunometabolic alterations in the context of immune regulation. Exploring the intricate mechanisms of polyamine metabolism holds promise for advancing our understanding of disease processes and developing potential innovative therapeutic interventions.

Keywords: Cancer; HIV; Immune regulation; Immunometabolism; Polyamines; Tumorigenesis

DOI: https://doi.org/10.33696/immunology.6.206

medRxiv. 2024 Dec 13. pii: 2024.12.12.24318845. [Epub ahead of print]

Androgen receptor drives polyamine synthesis creating a vulnerability for prostate cancer.

Supraphysiological androgen (SPA) treatment can paradoxically restrict growth of castration-resistant prostate cancer with high androgen receptor (AR) activity, which is the basis for use of Bipolar Androgen Therapy (BAT) for patients with this disease. While androgens are widely appreciated to enhance anabolic metabolism, how SPA-mediated metabolic changes alter prostate cancer progression and therapy response is unknown. Here, we report that SPA markedly increased intracellular and secreted polyamines in prostate cancer models. This occurred through AR binding at enhancer sites upstream of the ODC1 promoter to increase abundance of ornithine decarboxylase (ODC), a rate-limiting enzyme of polyamine synthesis, and de novo synthesis of polyamines from arginine. SPA-stimulated polyamines enhance prostate cancer fitness, as dCas9-KRAB-mediated inhibition of AR regulation of ODC1 or direct ODC inhibition by difluoromethylornithine (DFMO) increased efficacy of SPA. Mechanistically, this occurred in part due to increased activity of S-adenosylmethionine decarboxylase 1 (AMD1), which was stimulated both by AR and by loss of negative feedback by polyamines, leading to depletion of its substrate S-adenosylmethionine and global protein methylation. These data provided the rationale for a clinical trial testing the safety and efficacy of BAT in combination with DFMO for patients with metastatic castration-resistant prostate cancer. Pharmacodynamic studies of this drug combination in the first five patients on trial indicated that the drug combination resulted in effective polyamine depletion in plasma. Thus, the AR potently stimulates polyamine synthesis, which constitutes a vulnerability in prostate cancer treated with SPA that can be targeted therapeutically.

DOI: https://doi.org/10.1101/2024.12.12.24318845

ACS Omega. 2024 Dec 17. 9(50): 49887-49898

A Structurally Diverse Compound Screening Library to Identify Substrates for Diamine, Polyamine, and Related Acetyltransferases.

Hazel Leiva, Pamela L Caro De Silva, Ron Painter, Van Thi Bich Le, Patricia Uychoco, Daniel Figueroa Paniagua, Michael Endres, Natalia Maltseva, Andrzej Joachimiak, Misty L Kuhn.

Spermidine/spermine N-acetyltransferases (SSATs) and other types of polyamine acetyltransferases (PAATs) acetylate diamines and/or polyamines. These enzymes are evolutionarily related and belong to the Gcn5-related N-acetyltransferase (GNAT) superfamily, yet we lack a fundamental understanding of their substrate specificity and/or promiscuity toward different compounds. Many of these enzymes are known or are predicted to acetylate polyamines, but in the cell there are other types of compounds that contain moieties derived from polyamines that may be the native substrates for these enzymes. To learn more about the identity of substrates that are acetylated, we selected and screened 17 different GNAT enzymes for activity toward a set of structurally diverse compounds that contained different types of amine moieties (e.g., aminopropyl, aminobutyl, etc.). These compounds included diamines, triamines, and polyamines containing primary amino groups, and they had structural diversity with variation of the chain length and presence or absence of internal amino groups and other functional groups. We found 12 of the 17 enzymes acetylated at least one of the compounds. Some enzymes were selective toward acetylating only one compound while others exhibited substrate promiscuity toward numerous compounds. Our experimental results ultimately allowed us to pinpoint specific substrates that could be further investigated to more fully understand substrate specificity versus promiscuity of GNAT enzymes and the role of acetylated small molecules in cells.

DOI: https://doi.org/10.1021/acsomega.4c08743