title: The ER UDPase ENTPD5 promotes protein N-glycosylation, the Warburg effect, and proliferation in the PTEN pathway.
abstract: 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.
authors.affiliation: Howard Hughes Medical Institute, Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, 75390, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Fang
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Shen
authors.forename: Song
authors.initials: S
authors.lastname: Huang
authors.forename: Liping
authors.initials: L
authors.lastname: Zhao
authors.forename: She
authors.initials: S
authors.lastname: Chen
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wang
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000332:Aerobiosis; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006019:Glycolysis; D006031:Glycosylation; D006157:Guanosine Monophosphate / Q000378:metabolism; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D051058:Oncogene Protein v-akt / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D011755:Pyrophosphatases; D014183:Transplantation, Heterologous; D014542:Uridine Monophosphate / Q000378:metabolism
chemical_list: D015513:Oncogene Proteins; C485537:Pcph protein, mouse; D006157:Guanosine Monophosphate; D000255:Adenosine Triphosphate; D014542:Uridine Monophosphate; D051058:Oncogene Protein v-akt; D051059:PTEN Phosphohydrolase; C117634:ENTPD5 protein, human; D011755:Pyrophosphatases