title: Insulin receptor substrate-2 regulates aerobic glycolysis in mouse mammary tumor cells via glucose transporter 1.
abstract: The insulin receptor substrate (IRS) proteins are cytoplasmic adaptor molecules that function as signaling intermediates downstream of activated cell surface receptors. Based on data implicating IRS-2 but not IRS-1 in breast cancer invasion, survival, and metastasis, we assessed the contribution of IRS-1 and IRS-2 to aerobic glycolysis, which is known to impact tumor growth and progression. For this purpose, we used tumor cell lines derived from transgenic mice that express the polyoma virus middle T antigen (PyV-MT) in the mammary gland and that are wild-type (WT) or null for either Irs-1 (Irs-1-/-) or Irs-2 (Irs-2-/-). Aerobic glycolysis, as assessed by the rate of lactic acid production and glucose consumption, was diminished significantly in Irs-2-/- cells when compared with WT and Irs-1-/- cells. Expression of exogenous Irs-2 in Irs-2-/- cells restored the rate of glycolysis to that observed in WT cells. The transcription factor FoxO1 does not appear to be involved in Irs-2-mediated glycolysis. However, Irs-2 does regulate the surface expression of glucose transporter 1 (Glut1) as assessed by flow cytometry using a Glut1-specific ligand. Suppression of Glut1 expression inhibits Irs-2-dependent invasion, which links glycolysis to mammary tumor progression. Irs-2 was shown to be important for mammalian target of rapamycin (mTor) activation, and Irs-2-dependent regulation of Glut1 surface expression is rapamycin-sensitive. Collectively, our data indicate that Irs-2, but not Irs-1, promotes invasion by sustaining the aerobic glycolysis of mouse mammary tumor cells and that it does so by regulating the mTor-dependent surface expression of Glut1.
authors.affiliation: Department of Cancer Biology and Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Pankratz
authors.forename: Ernest Y
authors.initials: EY
authors.lastname: Tan
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Fine
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Mercurio
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Shaw
mesh_terms: D000332:Aerobiosis; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness / Q000473:pathology; D009362:Neoplasm Metastasis / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
chemical_list: D002352:Carrier Proteins; D005947:Glucose; D051272:Glucose Transporter Type 1; D055504:Insulin Receptor Substrate Proteins; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D058570:TOR Serine-Threonine Kinases; C546843:mTOR protein, mouse