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  • mct inhibitor br Serine glycine and one carbon metabolism Al

    2023-09-18


    Serine/glycine and one-carbon metabolism Altered serine metabolism in tumors was noted nearly half a century ago, and elevated flux through the de novo serine synthesis pathway (SSP) is a common phenomenon in cancer mct inhibitor [43]. The SSP branches from glycolysis at the point of 3-phosphoglycerate and involves three sequential reactions, catalyzed by 3-phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase (PSAT)1 and phosphoserine phosphatase (PSPH) (Fig. 3a). Even though up to 10% of glycolytic carbon can be diverted into this pathway [44], exogenous serine is still the third most rapidly consumed nutrient by cultured cancer cells [4,5]. Serine can be converted to glycine by serine hydroxymethyltransferases (cytosolic SHMT1 or mitochondrial SHMT2), donating a one-carbon unit to the folate pool which can ultimately be used in nucleotide biosynthesis (Fig. 3b). Glycine in turn is required for nucleotide biosynthesis, directly supplying carbons for de novo purine biosynthesis, or donating a one-carbon unit to the folate pool via the mitochondrial glycine cleavage system (Fig. 3b). Although glycine consumption was reported to correlate with proliferation rate [4], others have suggested that rapidly proliferating cells switch to glycine consumption only after exhausting exogenous serine [45]. Illustrating the importance of serine/glycine metabolism for oncogenic growth, TP53-null colorectal carcinoma cells cultured in serine-free medium exhibit oxidative stress and severely impaired proliferation and viability [45]. Because serine and glycine are nonessential amino acids, chronic depletion resulting from serine/glycine-free diets can be tolerated in vivo. Mice fed diets lacking serine and glycine display reduced colorectal xenograft tumor sizes and survive longer than mice fed control diets, indicating that therapeutic use of serine/glycine depletion is worthy of further investigation [45]. Mitochondrial SHMT2 is the primary catalyst for glycine production from serine, and one-carbon units are generated exclusively in mitochondria in most cultured cells (Fig. 3b) [6,45]. Furthermore, SHMT2 is one of the most frequently overexpressed ‘metabolic genes’ in human tumors [46], and its knockdown severely impairs proliferation of cultured cancer cells [4]. Paradoxically, SHMT2 supports tumorigenesis under hypoxia in part by maintaining low intracellular serine levels. Serine is an allosteric activator of pyruvate kinase isoform M2 (PKM2) (Fig. 3a), and therefore when intracellular serine is depleted PKM2 activity is suppressed and glycolytic intermediates accumulate [6]. By maintaining low serine concentrations, SHMT2 ensures low PKM2 activity and thus limits pyruvate supply for the TCA cycle (and consequent reactive oxygen species generation), providing a profound survival advantage for hypoxic glioma cells [47]. The survival advantage endowed by SHMT2 under hypoxia is dependent on clearance of the glycine product by the mitochondrial glycine cleavage system (GCS), and in particular the glycine decarboxylase (GLDC) component [47]. Notably, GLDC is overexpressed in some human cancers, and is reported to be one of the most upregulated genes in tumor-initiating cells isolated from non-small-cell lung cancer tumors [48]. SHMT2 and GLDC have been proposed as attractive therapeutic targets, and strategies to inhibit these enzymes are being pursued [6]. In 2011 it was discovered that the gene encoding PHGDH, which catalyzes the first reaction branching from glycolysis in the SSP (Fig. 3a), is recurrently amplified in a subset of human cancers including breast tumors, where PHGDH amplification or overexpression is associated with triple-negative/basal subtypes and poor prognosis [44,49]. An RNAi-based loss-of-function screen in a human breast cancer xenograft model identified PHGDH as one of 16 metabolic genes required for in vivo tumorigenesis [49]. Knockdown of PHGDH in cancer cell lines with high expression severely impairs serine biosynthesis and cell proliferation. Reciprocally, ectopic expression of PHGDH in nontumorigenic MCF-10A cells induces some characteristics of cellular transformation [44,49]. Importantly, genetic loss of PHGDH in cancer cells cannot be rescued by supplemental serine or glycine (even though intracellular serine levels are restored), indicating that the SSP has a crucial role beyond generating serine [49]. The underlying mechanism for this finding is still unresolved [43].