bims-meprid 2024-06-23 papers

Issue of 2024‒06‒23
three papers selected by
Alessandro Carrer, Veneto Institute of Molecular Medicine

Mol Carcinog. 2024 Jun 18.

ATP citrate lyase promotes the progression of hepatocellular carcinoma by activating the REGγ-proteasome pathway.

Qihong Cai, Honghua Zhu, Yile Dai, Qingqing Zhou, Qiyu Zhang, Qiandong Zhu.

The search for novel tumor biomarkers and targets is of significant importance for the early clinical diagnosis and treatment of Hepatocellular Carcinoma (HCC). The mechanisms by which ATP citrate lyase (ACLY) promotes HCC progression remain unclear, and the connection between ACLY and REGγ has not been reported in the literature. In vitro, we will perform overexpression/knockdown of ACLY or overexpression/knockdown of REGγ to investigate the impact of ACLY on HCC cells and its underlying mechanisms. In vivo, we will establish mouse tumor models with overexpression/knockdown of ACLY or overexpression/knockdown of REGγ to study the effect of ACLY on mouse tumors and its mechanisms. Firstly, ACLY overexpression upregulated REGγ expression and activated the REGγ-proteasome pathway, leading to changes in the expression of downstream signaling pathway proteins. This promoted HCC cell proliferation, invasion, and migration in vitro, as well as tumor growth and metastasis in vivo. Secondly, ACLY overexpression increased acetyl-CoA production, upregulated the acetylation level of the REGγ promoter region histone H3K27ac, and subsequently induced REGγ expression. Lastly, enhanced acetylation of the REGγ promoter region histone H3K27ac resulted in upregulated REGγ expression, activation of the REGγ-proteasome pathway, changes in downstream signaling pathway protein expression, and promotion of HCC cell proliferation, invasion, and migration in vitro, as well as tumor growth and metastasis in vivo. Conversely, REGγ knockdown reversed these effects. ACLY and REGγ may serve as potential biomarkers and clinical therapeutic targets for HCC.

Keywords: ATP citrate lyase; H3K27ac; REGγ; hepatocellular carcinoma; proteasome pathway

DOI: https://doi.org/10.1002/mc.23777

Immunity. 2024 Jun 19. pii: S1074-7613(24)00305-4. [Epub ahead of print]

A metabolic switch orchestrated by IL-18 and the cyclic dinucleotide cGAMP programs intestinal tolerance.

Randall T Mertens, Aditya Misra, Peng Xiao, Seungbyn Baek, Joseph M Rone, Davide Mangani, Kisha N Sivanathan, Adedamola S Arojojoye, Samuel G Awuah, Insuk Lee, Guo-Ping Shi, Boryana Petrova, Jeannette R Brook, Ana C Anderson, Richard A Flavell, Naama Kanarek, Martin Hemberg, Roni Nowarski.

Tissues are exposed to diverse inflammatory challenges that shape future inflammatory responses. While cellular metabolism regulates immune function, how metabolism programs and stabilizes immune states within tissues and tunes susceptibility to inflammation is poorly understood. Here, we describe an innate immune metabolic switch that programs long-term intestinal tolerance. Intestinal interleukin-18 (IL-18) stimulation elicited tolerogenic macrophages by preventing their proinflammatory glycolytic polarization via metabolic reprogramming to fatty acid oxidation (FAO). FAO reprogramming was triggered by IL-18 activation of SLC12A3 (NCC), leading to sodium influx, release of mitochondrial DNA, and activation of stimulator of interferon genes (STING). FAO was maintained in macrophages by a bistable switch that encoded memory of IL-18 stimulation and by intercellular positive feedback that sustained the production of macrophage-derived 2'3'-cyclic GMP-AMP (cGAMP) and epithelial-derived IL-18. Thus, a tissue-reinforced metabolic switch encodes durable immune tolerance in the gut and may enable reconstructing compromised immune tolerance in chronic inflammation.

Keywords: IL-18; SLC12A3; bistable circuit; cGAMP; fatty acid oxidation; immunometabolism; intestinal tolerance; macrophage; metabolic reprogramming; metabolic switch

DOI: https://doi.org/10.1016/j.immuni.2024.06.001

EMBO Rep. 2024 Jun 21.

Lactate supports cell-autonomous ECM production to sustain metastatic behavior in prostate cancer.

Luigi Ippolito, Assia Duatti, Marta Iozzo, Giuseppina Comito, Elisa Pardella, Nicla Lorito, Marina Bacci, Erica Pranzini, Alice Santi, Giada Sandrini, Carlo V Catapano, Sergio Serni, Pietro Spatafora, Andrea Morandi, Elisa Giannoni, Paola Chiarugi.

Extracellular matrix (ECM) is a major component of the tumor environment, promoting the establishment of a pro-invasive behavior. Such environment is supported by both tumor- and stromal-derived metabolites, particularly lactate. In prostate cancer (PCa), cancer-associated fibroblasts (CAFs) are major contributors of secreted lactate, able to impact on metabolic and transcriptional regulation in cancer cells. Here, we describe a mechanism by which CAF-secreted lactate promotes in PCa cells the expression of genes coding for the collagen family. Lactate-exploiting PCa cells rely on increased α-ketoglutarate (α-KG) which activates the α-KG-dependent collagen prolyl-4-hydroxylase (P4HA1) to support collagen hydroxylation. De novo synthetized collagen plays a signaling role by activating discoidin domain receptor 1 (DDR1), supporting stem-like and invasive features of PCa cells. Inhibition of lactate-induced collagen hydroxylation and DDR1 activation reduces the metastatic colonization of PCa cells. Overall, these results provide a new understanding of the link between collagen remodeling/signaling and the nutrient environment exploited by PCa.

Keywords: CAFs; Collagen Hydroxylation; Collagen Signaling; Lactate Metabolism

DOI: https://doi.org/10.1038/s44319-024-00180-z