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Small molecule activation of PKM in cancer cells induces serine auxotrophy

ABSTRACT: Proliferating tumor cells use aerobic glycolysis to support their high metabolic demands. Paradoxically, increased glycolysis is often accompanied by expression of the lower activity PKM isoform, effectively constraining lower glycolysis. Here, we report the discovery of novel PKM activators with a unique allosteric binding mode. Characterization of how these compounds impact cancer cells revealed an unanticipated link between glucose and amino acid metabolism. PKM activation resulted in a metabolic rewiring of cancer cells manifested by a profound dependency on the non-essential amino acid serine for continued cell proliferation. Induction of serine auxotrophy by PKM activation was accompanied by reduced carbon flow into the serine biosynthetic pathway and increased expression of high affinity serine transporters. These data support the hypothesis that PKM expression confers metabolic flexibility to cancer cells that allows adaptation to nutrient stress.

ORGANISM(S): Homo sapiens

PROVIDER: GSE40191 | GEO | 2012/12/20

SECONDARY ACCESSION(S): PRJNA173063

REPOSITORIES: GEO

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Small molecule activation of PKM in cancer cells induces serine auxotrophy

Project description:Proliferating tumor cells use aerobic glycolysis to support their high metabolic demands. Paradoxically, increased glycolysis is often accompanied by expression of the lower activity PKM isoform, effectively constraining lower glycolysis. Here, we report the discovery of novel PKM activators with a unique allosteric binding mode. Characterization of how these compounds impact cancer cells revealed an unanticipated link between glucose and amino acid metabolism. PKM activation resulted in a metabolic rewiring of cancer cells manifested by a profound dependency on the non-essential amino acid serine for continued cell proliferation. Induction of serine auxotrophy by PKM activation was accompanied by reduced carbon flow into the serine biosynthetic pathway and increased expression of high affinity serine transporters. These data support the hypothesis that PKM expression confers metabolic flexibility to cancer cells that allows adaptation to nutrient stress. A549 cancer cells were treated with compound-16 for up to 24 hours in the presence and absence of serine in the media.

2012-12-20 | E-GEOD-40191 | biostudies-arrayexpress

CD28-CBCA driven PKM splicing licenses CD8 T cell glycolysis and effector function

Project description:T cells stimulated in the absence of CD28 costimulation are functionally anergic, characterized by reduced glucose metabolism and ability to produce effector cytokines. Surprisingly, previous studies have shown relatively few CD28-specific changes in gene transcription upon costimulation. Using mice expressing mutations in the CD28 cytoplasmic tail, we show a major effect of CD28 costimulation is alternative splicing of numerous genes including the glycolytic enzyme pyruvate kinase (Pkm), which is preferentially spliced from Pkm1 to Pkm2 upon stimulation. PKM2 is dispensable for T cell activation, but necessary for CD8+ T cells to utilize aerobic glycolysis, produce effector cytokines, and provide anti-tumor immunity. Mechanistically, CD28 regulates expression of the Cap-Binding Complex adaptor protein ARS2, which binds Pkm splicing factors and facilitates their interaction with the elongating transcript. Data suggest a major function of CD28 costimulation is control of RNA biogenesis in support of T cell transcriptome remodeling and acquisition of effector function.

2023-09-01 | GSE168824 | GEO

Homo sapiens

Project description:Small molecule activation of PKM in cancer cells induces serine auxotrophy

| PRJNA173063 | ENA

CD28-CBCA driven PKM splicing licenses CD8 T cell glycolysis and effector function

Project description:CD28-CBCA driven PKM splicing licenses CD8 T cell glycolysis and effector function

| PRJNA714096 | ENA

Pyruvate Kinase M (PKM) binds ribosomes in a poly-ADP ribosylation dependent manner to induce translational stalling

Project description:In light of the numerous studies identifying post-transcriptional regulators on the surface of the endoplasmic reticulum (ER), we ask whether there are factors that regulate compartment specific mRNA translation in human cells. Using a proteomic survey of spatially regulated polysome interacting proteins, we identified the glycolytic enzyme Pyruvate Kinase M (PKM) as a cytosolic (i.e., ER-excluded) polyribosome interactor and investigate how it influences mRNA translation. We discovered that the PKM-polysome interaction is directly regulated by ADP levels–providing a link between carbohydrate metabolism and mRNA translation. By performing enhanced crosslinking immunoprecipitation-sequencing (eCLIP-seq), we found that PKM crosslinks to mRNA sequences that are immediately downstream of regions that encode for lysine and glutamate enriched tracts. Additionally, PKM binding to ribosomes causes translational stalling near these lysine and glutamate encoding sequences. Lastly, we find that PKM recruitment to polysomes is dependent on poly-ADP ribosylation. Overall, our study uncovers a novel role for PKM in posttranscriptional gene regulation, linking cellular metabolism and mRNA translation, and provides the first reported evidence of nascent chains being co-translationally modified with poly-ADP ribose.

2022-05-16 | GSE202881 | GEO

RBMX suppresses tumorigenicity and progression of bladder cancer via interaction with hnRNP A1 protein to regulate PKM alternative splicing

Project description:Bladder cancer (BCa) is one of the most common malignant tumors of urinary system and has high incidence rate and mortality but there is a lack of effective treatment. Therefore, an in-depth study of the molecular mechanisms involved in BCa is of great significance for improving the survival of patients with advanced BCa. We found that the expression of RBMX was significantly declined in BCa, especially in muscle-invasive BCa. BCa patients with low levels of RBMX had poor prognoses. By in vitro and in vivo experiments, RBMX was shown to inhibit BCa cells growth and metastasis. Co-IP coupled with MS and GO analysis identified hnRNP A1 as a RBMX-binding protein. Mechanistically, RBMX competitively bond to the RGG box of hnRNP A1 and antagonized the hnRNP A1-mediated regulation of PKM splicing by blocking the binding of the RGG motif of hnRNP A1 to the sequences flanking PKM exon 9, resulting in downregulation of PKM2 and upregulation of PKM1. By decreasing the PKM2/PKM1 ratio, RBMX suppressed BCa cells aerobic glycolysis, which further inhibited tumorigenicity and progression of BCa.

2020-11-23 | GSE150548 | GEO

Transcriptomic analysis of Campylobacter jejuni grown in medium containing serine as a main energy source

Project description:Campylobacter jejuni is one of the most important causes of food-borne diseases in industrialized countries. It is known that amino acids are important nutrient source for this pathogen, because C. jejuni lacks enzymes related to glycolysis. However, the characteristics on metabolism of C. jejuni grown in the nutrient restricted medium with a specific amino acid is not fully elucidated. This study shows that C. jejuni NCTC11168 grew well in the nutrient restricted medium containing serine, aspartate, glutamate, and proline. The single subtraction of serine significantly reduced the growth, while three other amino acids did not, suggesting the priority of serine among the four amino acids. In the transcriptomic analysis of C. jejuni NCTC11168 grown in medium with serine as a main energy source. Serine seemed to be sensed by some chemoreceptors and the C. jejuni might reached an adaptation stage with active growth. That is, the expression of flagellar assembly components was downregulated and the biosynthesis of multiple amino acids and nucleotide sugars were upregulated. These data suggest the higher requirement of serine as a nutrient of C. jejuni NCTC11168.

2018-09-17 | GSE119472 | GEO

SAM68 promotes Lung adenocarcinoma tumorigenesis by regulating cancer metabolic conversion through alternative splicing

Project description:The metabolic conversion of oxidative phosphorylation to glycolysis provides tumor cells with energy and biosynthetic substrates, thereby promoting tumorigenesis and malignant progression. However, the mechanisms controlling the tumor metabolic switch is still not entirely clear. Here we demonstrate that SAM68 (gene name: KHDRBS1) as a splicing regulatory factor is frequently overexpressed in Lung adenocarcinoma (LUAD) and negatively correlated with the prognosis of LUAD patients. we find SAM68 promotes LUAD cells tumorigenesis and metastasis both in vitro and in vivo by regulating cancer metabolic switch. SAM68 drives cancer metabolism by mediating alternative splicing of Pyruvate kinase (PKM) pre-mRNAs, finally promoting the formation of PKM2. Mechanically, Sam68 interacted with the splicing repressor hnRNP A1, and depletion of hnRNP A1 or mutations that impair this interaction attenuated the PKM splicing regulation. Together, our work demonstrates key roles of SAM68 in the cancer metabolic conversion by regulating alternative splicing and SAM68 may be a promising therapeutic target for treating LUAD.This project looks into how SAM68 levels affect cancer cell phenotype in vitro

2020-11-04 | GSE149120 | GEO

Expression time course of yeast grown in a minimal medium

Project description:Time course of exponentially growing yeast cells Fermenting glucose in the presence of enough oxygen to support respiration, known as aerobic glycolysis, is believed to maximize growth rate. We observed increasing aerobic glycolysis during exponential growth, suggesting additional physiological roles for aerobic glycolysis. We investigated such roles in yeast batch cultures by quantifying O2 consumption, CO2 production, amino acids, mRNAs, proteins, posttranslational modifications, and stress sensitivity in the course of nine doublings at constant rate. During this course, the cells support a constant biomass-production rate with decreasing rates of respiration and ATP production but also decrease their stress resistance. As the respiration rate decreases, so do the levels of enzymes catalyzing rate-determining reactions of the tricarboxylic-acid cycle (providing NADH for respiration) and of mitochondrial folate-mediated NADPH production (required for oxidative defense). The findings demonstrate that exponential growth can represent not a single metabolic/physiological state but a continuum of changing states and that aerobic glycolysis can reduce the energy demands associated with respiratory metabolism and stress survival.

2014-04-24 | GSE56773 | GEO

D-Serine activates glycolysis via mTOR pathway in kidney remodeling and suppresses onset of diabetes

Project description:D-Serine, a long-term undetected enantiomer of serine1,2, is a novel biomarker that reflects kidney function and disease activity3-5 and has unclear physiological functions. Here we show that D-serine is a physiological molecule that promotes tissue remodeling and suppresses the onset of diabetes. D-serine is quickly and dominantly distributed to the kidney upon injection in mice, suggesting that the kidney is a key target organ. Unilateral nephrectomy in human living kidney donors decreases urinary excretion and thus increases the blood level of D-serine, which in turn promotes the compensatory enlargement of the remnant kidney in mouse model. D-Serine activates cell cycle for tissue remodeling through an mTOR-related pathway, which promotes metabolic reprograming to glycolytic activation. In rodent diabetic model, D-serine promotes glycolysis in the kidney and suppresses the surge of blood glucose levels. D-Serine has physiological activity that influences kidney function and maintains metabolic homeostasis to reduce diabetic propensity.

2022-04-07 | GSE155475 | GEO

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