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Cancer-derived branched-chain ketoacids modulate macrophage polarization and metabolic reprogramming

ABSTRACT: This study aims to uncover the effects of cancer-derived branched-chain ketoacids on macrophage polarization and the underlying mechanism. We uncovered the global responses of branched-chain ketoacids-stimulated macrophages by proteomics analysis. Functional enrihment analysis indicated that these ketoacids significantly altered macrophage metabolism, apoptosis and phagocytosis.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Bone Marrow, Macrophage

SUBMITTER: Zhengnan Cai

LAB HEAD: Wolfram Weckwerth

PROVIDER: PXD032100 | Pride | 2022-10-04

REPOSITORIES: Pride

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			Action	DRS
	Combined_BCKAs.xlsx	Xlsx
	G01DMEM.raw	Raw
	G02DMEM.raw	Raw
	G03AE.raw	Raw
	G07_AKIV.raw	Raw

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Branched-chain ketoacids derived from cancer cells modulate macrophage polarization and metabolic reprogramming

Project description:<p>Macrophages are prominent immune cells in the tumor microenvironment that can be educated into pro-tumoral phenotype by tumor cells to favor tumor growth and metastasis. The mechanisms that mediate a mutualistic relationship between tumor cells and macrophages remain poorly characterized. Here, we have shown <em>in vitro</em> that different human and murine cancer cell lines release branched‐chain α‐ketoacids (BCKAs) into the extracellular milieu, which influence macrophage polarization in an monocarboxylate transporter 1 (MCT1)‐dependent manner. We found that α‐ketoisocaproate (KIC) and α‐keto‐β‐methylvalerate (KMV) induced a pro‐tumoral macrophage state, whereas α‐ketoisovalerate (KIV) exerted a pro‐inflammatory effect on macrophages. This process was further investigated by a combined metabolomics/proteomics platform. KMV and KIC altered macrophage tricarboxylic acid (TCA) cycle intermediates and increased polyamine metabolism. Proteomic and pathway analyses revealed that the three BCKAs, especially KMV, exhibited divergent effects on the inflammatory signal pathways, phagocytosis, apoptosis and redox balance. These findings uncover cancer‐derived BCKAs as novel determinants for macrophage polarization with potential to be selectively exploited for optimizing antitumor immune responses.</p>

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Project description:To study the role of branched-chain amino acid metabolism in neural stem cells we generated two primary neural stem cell culture lines in which on was deleted for the Ppm1k gene using floxed cells and adenovirus delviered cre-recombinase.

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Reprograming of Proteasomal Degradation by Branched Chain Amino Acid Metabolism

Project description:Branched‐chain amino acid (BCAA) metabolism is a central hub for energy production and regulation of numerous physiological processes. Controversially, both increased and decreased levels of BCAAs are associated with longevity. Using genetics and multi‐omics analyses in Caenorhabditis elegans, we identified adaptive regulation of the ubiquitin‐proteasome system (UPS) in response to defective BCAA catabolic reactions after the initial transamination step. Worms with impaired BCAA metabolism show a slower turnover of a GFP‐based proteasome substrate, which is suppressed by loss‐of‐function of the first BCAA catabolic enzyme, the branched‐chain aminotransferase BCAT‐1. The exogenous supply of BCAA‐derived carboxylic acids, which are known to accumulate in the body fluid of patients with BCAA metabolic disorders, is sufficient to regulate the UPS. The link between BCAA intermediates and UPS function presented here sheds light on the unexplained role of BCAAs in the aging process and opens future possibilities for therapeutic interventions.

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Reprograming of Proteasomal Degradation by Branched Chain Amino Acid Metabolism

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RNA sequencing of human marcrophages treated with lipopolysaccharide (LPS) for 8 hours, with or without BCAT1 inhibitor (ERG240)

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