bims-polyam 2023-01-15 papers

Issue of 2023–01–15
four papers selected by
Sebastian J. Hofer, University of Graz

Immunohorizons. 2023 Jan 01. 7(1): 41-48

The Polyamine Putrescine Is a Positive Regulator of Group 3 Innate Lymphocyte Activation.

Group 3 innate lymphocytes (ILC3s) rapidly respond to invading pathogens or inflammatory signals, which requires shifting cellular metabolic demands. Metabolic adaptations regulating ILC3 function are not completely understood. Polyamines are polycationic metabolites that have diverse roles in cellular functions and in immunity regulate immune cell biology, including Th17 cells. Whether polyamines play a role in ILC3 activation is unknown. In this article, we report that the polyamine synthesis pathway is important for ILC3 activation. IL-23-activated mouse ILC3s upregulate ornithine decarboxylase, the enzyme catalyzing the rate-limiting step of the conversion of ornithine to putrescine in polyamine synthesis, with a subsequent increase in putrescine levels. Inhibition of ornithine decarboxylase via a specific inhibitor, α-difluoromethylornithine, reduced levels of IL-22 produced by steady-state or IL-23-activated ILC3s in a putrescine-dependent manner. Thus, the polyamine putrescine is a positive regulator of ILC3 activation. Our results suggest that polyamines represent a potential target for therapeutic modulation of ILC3 activation during infection or inflammatory disorders.

DOI: https://doi.org/10.4049/immunohorizons.2200097

Int J Mol Sci. 2022 Dec 21. pii: 101. [Epub ahead of print]24(1):

Quantitative Metabolomics to Explore the Role of Plasma Polyamines in Colorectal Cancer.

Donatella Coradduzza, Caterina Arru, Nicola Culeddu, Antonella Congiargiu, Emanuela Gigliola Azara, Antonio Mario Scanu, Angelo Zinellu, Maria Rosaria Muroni, Vincenzo Rallo, Serenella Medici, Ciriaco Carru, Andrea Angius, Maria Rosaria De Miglio.

Colorectal cancer (CRC) is one of the major public health and socio-economic problems, which management demands the development of non-invasive screening tests. Assessment of circulating polyamines could be a valuable tool, although analytical problems still preclude its clinical practice. We exploited ultra-high-resolution liquid chromatography and mass spectrometry, as a highly sensitive and innovative method, to profile eleven polyamines, including spermine and spermidine with their acetylated forms. These data together with an evaluation of the inflammatory indexes might represent suitable biomarkers for the identification of CRC patients. The statistical models revealed good discrimination in distinguishing CRC patients from healthy subjects. The plasma assessment of ornithine and acetylspermine, as well as lymphocyte/platelet ratio, revealed helpful information on the progression of CRC. The combined profiles of circulating polyamines and inflammatory indexes, together with the application of an innovative technology, could represent a valuable tool for discriminating patients from different clinical groups.

Keywords: agmatine; biomarker; colorectal cancer; inflammatory indexes; polyamine

DOI: https://doi.org/10.3390/ijms24010101

Am J Cancer Res. 2022 ;12(12): 5516-5531

Protein tyrosine phosphatase PTPN2 regulates TGF-β signaling through Smad4 dephosphorylation.

Sujing Shi, Dewei Xu, Shuchen Gu, Ningyi Xu, Pinglong Xu, Jin Cao, Xin-Hua Feng.

Transforming Growth Factor beta (TGF-β) is a multifunctional cytokine that regulates cell proliferation, differentiation, and apoptosis. Dysregulation of the TGF-β signaling is one of the major mechanisms underlying tumor progression. We have previously reported that anaplastic lymphoma kinase (ALK) phosphorylates Smad4 at Tyr95, which compromises the DNA-binding ability of Smad4 and thus renders ALK-positive cancer cells resistant to TGF-β tumor-suppressive action. In this study, we demonstrated that tyrosine phosphatase PTPN2 positively regulated TGF-β signaling through dephosphorylating Smad4 at the Tyr95 site. Both in vitro and cell-based assays revealed that PTPN2 bound to and dephosphorylated Smad4, thereby preserving the DNA-binding ability of Smad4. Furthermore, overexpression of PTPN2 restored TGF-β transcriptional and growth inhibitory responses in ALK-positive cancer cells. Consistently, Spermidine, an activator of PTPN2, also promoted TGF-β-induced gene expression, apoptosis, and anti-proliferation effect. Taken together, we revealed that PTPN2 functioned as a tumor suppressor to antagonize the inhibitory effect of tyrosine phosphorylation of Smad4 and to ensure the proper TGF-β growth inhibitory signaling in cancer cells.

Keywords: ALK; Smad; spermidine; tumor suppressor; tyrosine phosphorylation