ArticleCancer & metabolism2019
Cysteine catabolism and the serine biosynthesis pathway support pyruvate production during pyruvate kinase knockdown in pancreatic cancer cells.
Article in Cancer & metabolism, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 41 citations in OpenAlex.
- Cellular homeostasis of N-acetylneuraminic acid and non-canonical sialic acids is mediated by human N-acetylneuraminate lyase.Glycobiology · 2026Article
- PHGDH mediated serine biosynthesis metabolism suppresses vascular calcification.Biology direct · 2026Article
- PHGDH is a targetable driver of PDAC progression.bioRxiv : the preprint server for biology · 2026Article
- The Current Applications of Metabolomics in Understanding Endometriosis: A Systematic Review.Metabolites · 2025Review
- PHGDH: a novel therapeutic target in cancer.Experimental & molecular medicine · 2024Review
- Article
- Pyruvate Kinase Activity Regulates Cystine Starvation Induced Ferroptosis through Malic Enzyme 1 in Pancreatic Cancer Cells.bioRxiv : the preprint server for biology · 2023Article
- Evaluating Metabolite-Based Biomarkers for Early Diagnosis of Pancreatic Cancer: A Systematic Review.Metabolites · 2023Review
- PKM2 deficiency exacerbates gram-negative sepsis-induced cardiomyopathy via disrupting cardiac calcium homeostasis.Cell death discovery · 2022Article
- Cysteine restriction-specific effects of sulfur amino acid restriction on lipid metabolism.Aging cell · 2022Article
- Pyruvate Kinase M2 Protects Heart from Pressure Overload-Induced Heart Failure by Phosphorylating RAC1.Journal of the American Heart Association · 2022Article
- The Association between Serum Serine and Glycine and Related-Metabolites with Pancreatic Cancer in a Prospective Cohort Study.Cancers · 2022Article
- Review
- Review
- Article
- Glycolysis in the progression of pancreatic cancer.American journal of cancer research · 2022Review
- The putative role of gut microbiota in cancer: Cysteine is a pivotal coin.Frontiers in gastroenterology (Lausanne, Switzerland) · 2022Review
- Single-Cell Transcriptome Reveals the Metabolic and Clinical Features of a Highly Malignant Cell Subpopulation in Pancreatic Ductal Adenocarcinoma.Frontiers in cell and developmental biology · 2022Article
- Development of a Novel Benzimidazole-Based Probe and Portable Fluorimeter for the Detection of Cysteine in Human Urine.Biosensors · 2021Article
- Overcoming chemoresistance by targeting reprogrammed metabolism: the Achilles' heel of pancreatic ductal adenocarcinoma.Cellular and molecular life sciences : CMLS · 2021Review
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundPancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with limited treatment options. Pyruvate kinase, especially the M2 isoform (PKM2), is highly expressed in PDAC cells, but its role in pancreatic cancer remains controversial. To investigate the role of pyruvate kinase in pancreatic cancer, we knocked down PKM2 individually as well as both PKM1 and PKM2 concurrently (PKM1/2) in cell lines derived from a
methodsWe used liquid chromatography tandem mass spectrometry (LC-MS/MS) to determine metabolic profiles of wildtype and PKM1/2 knockdown PDAC cells. We further used stable isotope-labeled metabolic precursors and LC-MS/MS to determine metabolic pathways upregulated in PKM1/2 knockdown cells. We then targeted metabolic pathways upregulated in PKM1/2 knockdown cells using CRISPR/Cas9 gene editing technology.
resultsPDAC cells are able to proliferate and continue to produce pyruvate despite PKM1/2 knockdown. The serine biosynthesis pathway partially contributed to pyruvate production during PKM1/2 knockdown: knockout of phosphoglycerate dehydrogenase in this pathway decreased pyruvate production from glucose. In addition, cysteine catabolism generated ~ 20% of intracellular pyruvate in PDAC cells. Other potential sources of pyruvate include the sialic acid pathway and catabolism of glutamine, serine, tryptophan, and threonine. However, these sources did not provide significant levels of pyruvate in PKM1/2 knockdown cells.
conclusionPKM1/2 knockdown does not impact the proliferation of pancreatic cancer cells. The serine biosynthesis pathway supports conversion of glucose to pyruvate during pyruvate kinase knockdown. However, direct conversion of serine to pyruvate was not observed during PKM1/2 knockdown. Investigating several alternative sources of pyruvate identified cysteine catabolism for pyruvate production during PKM1/2 knockdown. Surprisingly, we find that a large percentage of intracellular pyruvate comes from cysteine. Our results highlight the ability of PDAC cells to adaptively rewire their metabolic pathways during knockdown of a key metabolic enzyme.
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