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URL: https://pubmed.ncbi.nlm.nih.gov/30298120/

⇱ Mevalonate Metabolism in Cancer Stemness and Trained Immunity - PubMed

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Abstract

Mevalonate metabolism provides cancer and immune cells with diverse products to ensure cell functionality. Similar metabolic reprogramming that raises mevalonate metabolism to higher levels appears to drive both, epithelial mesenchymal transition (EMT) of cancer cells, a reverse differentiation program that generates cancer cells with stem cell properties, and immune cell training for increased responsiveness to secondary stimulation. In this review, we address how mevalonate metabolism supports cancer development and stemness on the one hand, and on the other promotes immune responsiveness. In view of this dual nature of mevalonate metabolism, strategies to manipulate this metabolic pathway as part of anti-cancer therapies require careful analysis of risks versus benefits.

Keywords: Wnt signaling; epithelial mesenchymal transition (EMT); mevalonate metabolism; stemness; trained immunity.

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Figure 1
Wnt/ß-catenin driven mevalonate metabolism promotes EMT. Mevalonate metabolism is fueled by glycolysis. Glucose-derived pyruvate enters the TCA cycle. Since some citrate is exported into the cytosol for lipogenesis (i.e., mevalonate metabolism and fatty acid synthesis), glutaminolysis generates α-ketoglutarate to replenish TCA cycle intermediates. Canonical Wnt signaling, which can be activated for instance in response to cilia loss, promotes the translocation of β-catenin to the nucleus, where it acts as coactivator of TCF factors in the transcription of target genes. In addition, ß-catenin may stimulate mevalonate metabolism by forming a complex with SREBP2 on the promoters of mevalonate pathway genes, including HMGCR (HMG-CoA reductase, the target of statins). In addition, β-catenin/TCF4 binds directly to the promoter of ZEB1, a key inducer of EMT, and activates its transcription. N-BPs, nitrogen-containing bisphosphonates.

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