SAICAR stimulates pyruvate kinase isoform M2 and promotes cancer cell survival in glucose-limited conditions
Open accessAbstract
Pyruvate kinase isoform M2 (PKM2) plays an important role in the growth and metabolic reprogramming of cancer cells in stress conditions. Here, we report that SAICAR (succinylaminoimidazolecarboxamide ribose-5'-phosphate, an intermediate of the de novo purine nucleotide synthesis pathway) specifically stimulates PKM2. Upon glucose starvation, cellular SAICAR concentration increased in an oscillatory manner and stimulated PKM2 activity in cancer cells. Changes in SAICAR amounts in cancer cells altered cellular energy level, glucose uptake, and lactate production. The SAICAR-PKM2 interaction also promoted cancer cell survival in glucose-limited conditions. SAICAR accumulation was not observed in normal adult epithelial cells or lung fibroblasts, regardless of glucose conditions. This allosteric regulation may explain how cancer cells coordinate different metabolic pathways to optimize their growth in the nutrient-limited conditions commonly observed in the tumor microenvironment.
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PKM2 can be allosterically activated by excess accumulation of other glucose metabolism byproducts including SAICAR, an intermediate of ribose-5-phosphate biosynthesis.
“In addition to serine, PKM2 can also be allosterically activated by excess accumulation of other byproducts of glucose metabolism including succinylaminoimidazolecarboxamide (SAICAR), an intermediate product of ribose-5-phosphate biosynthesis (Keller et al., 2012).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Keller et al., 2012
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References 26 · Cited by 228
- Authors
- Keller, K. E., Tan, I. S., & Lee, Y.-S.
- Affiliations
- Johns Hopkins University (US)
- National Institutes of Health (US)
- Corresponding author
- Lee, Young-Sam
- Venue
- Science
- Published
- 2012-11-23
- Volume
- 338
- Issue
- 6110
- Pages
- 1069-1072
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC3527123
- OpenAlex
- W1996646041
- Cited by
- 228
- References
- 26
- Citations by year
- 2026: 6 · 2025: 13 · 2024: 11 · 2023: 15 · 2022: 19 · 2021: 23 · 2020: 19 · 2019: 20 · 2018: 17 · 2017: 9 · 2016: 22 · 2015: 17 · 2014: 19 · 2013: 16 · 2012: 2
- FWCI
- 5.73
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of General Medical Sciences (T32GM007231)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Keywords
- SAICAR, PKM2, glucose deprivation, tumor cell survival, allosteric regulation, tumor metabolic reprogramming, tumor microenvironment, glucose uptake, lactic acid production, cellular energy metabolism
- MeSH terms
- Allosteric Regulation, Aminoimidazole Carboxamide, Cell Survival, Fibroblasts, Glucose, HeLa Cells, Humans, Neoplasms, Pyruvate Kinase, Recombinant Proteins, Ribonucleosides, Tumor Microenvironment
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