The ER UDPase ENTPD5 Promotes Protein N-Glycosylation, the Warburg Effect, and Proliferation in the PTEN Pathway
Open accessAbstract
PI3K and PTEN lipid phosphatase control the level of cellular phosphatidylinositol (3,4,5)-trisphosphate, an activator of AKT kinases that promotes cell growth and survival. Mutations activating AKT are commonly observed in human cancers. We report here that ENTPD5, an endoplasmic reticulum (ER) enzyme, is upregulated in cell lines and primary human tumor samples with active AKT. ENTPD5 hydrolyzes UDP to UMP to promote protein N-glycosylation and folding in ER. Knockdown of ENTPD5 in PTEN null cells causes ER stress and loss of growth factor receptors. ENTPD5, together with cytidine monophosphate kinase-1 and adenylate kinase-1, constitute an ATP hydrolysis cycle that converts ATP to AMP, resulting in a compensatory increase in aerobic glycolysis known as the Warburg effect. The growth of PTEN null cells is inhibited both in vitro and in mouse xenograft tumor models. ENTPD5 is therefore an integral part of the PI3K/PTEN regulatory loop and a potential target for anticancer therapy.
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Cells with activated PI3K/Akt upregulate the activity of ENTPD5, an endoplasmic reticulum enzyme involved in glycosylation reactions and linked to ATP hydrolysis.
“cells with activated PI3K/Akt upregulate the activity of ENTPD5, an endoplasmic reticulum enzyme involved in glycosylation reactions and linked to ATP hydrolysis (Fang et al., 2010)”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as Fang et al., 2010
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“This activity is linked to ATP hydrolysis in the cytosol and has a positive effect on glycolytic rates (Fang et al, 2010).”
BackgroundNADH binds and stabilizes the 26S proteasomes independent of ATP
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- Authors
- Fang, M., Shen, Z., Huang, S., Zhao, L., Chen, S., Mak, T. W., & Wang, X.
- Affiliations
- Howard Hughes Medical Institute (US)
- National Institute of Biological Sciences, Beijing (CN)
- Princess Margaret Cancer Centre (CA)
- Corresponding author
- Wang, Xiaodong
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2010-11
- Volume
- 143
- Issue
- 5
- Pages
- 711-724
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2108812570
- Cited by
- 222
- References
- 32
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 6 · 2023: 20 · 2022: 9 · 2021: 10 · 2020: 9 · 2019: 9 · 2018: 13 · 2017: 11 · 2016: 15 · 2015: 15 · 2014: 29 · 2013: 15 · 2012: 24
- FWCI
- 7.55
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 989 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5p01ca095471-10)
- National Cancer Institute (P01 CA95471)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- 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
- ENTPD5, N-glycosylation, Warburg effect, aerobic glycolysis, PTEN, phosphatidylinositol 3,4,5-trisphosphate, Akt, endoplasmic reticulum stress, protein folding, AK1, ATP hydrolysis cycle, cell proliferation, tumor growth, cancer therapy targets
- MeSH terms
- Adenosine Triphosphate, Aerobiosis, Animals, Endoplasmic Reticulum, Glycolysis, Glycosylation, Guanosine Monophosphate, Humans, Neoplasm Transplantation, Pyrophosphatases, Transplantation, Heterologous, Uridine Monophosphate, Oncogene Proteins, Cell Line, Tumor, Cell Proliferation, Oncogene Protein v-akt, PTEN Phosphohydrolase, Mice
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