title: Insulin-mediated signaling promotes proliferation and survival of glioblastoma through Akt activation.
abstract: BACKGROUND
  Metabolic complications such as obesity, hyperglycemia, and type 2 diabetes are associated with poor outcomes in patients with glioblastoma. To control peritumoral edema, use of chronic high-dose steroids in glioblastoma patients is common, which can result in de novo diabetic symptoms. These metabolic complications may affect tumors via profound mechanisms, including activation of insulin receptor (InsR) and the related insulin-like growth factor 1 receptor (IGF1R) in malignant cells.
  
  
  METHODS
  In the present study, we assessed expression of InsR in glioblastoma surgical specimens and glioblastoma response to insulin at physiologically relevant concentrations. We further determined whether genetic or pharmacological targeting of InsR affected oncogenic functions of glioblastoma in vitro and in vivo.
  
  
  RESULTS
  We showed that InsR was commonly expressed in glioblastoma surgical specimens and xenograft tumor lines, with mitogenic isoform-A predominating. Insulin at physiologically relevant concentrations promoted glioblastoma cell growth and survival, potentially via Akt activation. Depletion of InsR impaired cellular functions and repressed orthotopic tumor growth. The absence of InsR compromised downstream Akt activity, but yet stimulated IGF1R expression. Targeting both InsR and IGF1R with dual kinase inhibitors resulted in effective blockade of downstream signaling, loss of cell viability, and repression of xenograft tumor growth.
  
  
  CONCLUSIONS
  Taken together, our work suggests that glioblastoma is sensitive to the mitogenic functions of insulin, thus significant insulin exposure imposes risks to glioblastoma patients. Additionally, dual inhibition of InsR and IGF1R exhibits promise for treating glioblastoma.
authors.affiliation: Department of Neurological Surgery (Y.G., Y.M., R.C.T., S.W.C., J.W.), Department of Molecular Physiology and Biophysics (W.C.), Department of Neurology (S.W.C.), Department of Pathology, Microbiology and Immunology (B.C.M.), and Department of Cancer Biology and Department of Pharmacology, Vanderbilt University, Nashville, Tennessee (J.W.); Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio (M.S., J.D.L.); Department of Neuroscience and Pharmacology, Meharry Medical College, Nashville, Tennessee (S.L.); Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (J.N.S.).
authors.forename: Yuanying
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Department of Neurological Surgery (Y.G., Y.M., R.C.T., S.W.C., J.W.), Department of Molecular Physiology and Biophysics (W.C.), Department of Neurology (S.W.C.), Department of Pathology, Microbiology and Immunology (B.C.M.), and Department of Cancer Biology and Department of Pharmacology, Vanderbilt University, Nashville, Tennessee (J.W.); Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio (M.S., J.D.L.); Department of Neuroscience and Pharmacology, Meharry Medical College, Nashville, Tennessee (S.L.); Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (J.N.S.).
authors.forename: Yufang
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Neurological Surgery (Y.G., Y.M., R.C.T., S.W.C., J.W.), Department of Molecular Physiology and Biophysics (W.C.), Department of Neurology (S.W.C.), Department of Pathology, Microbiology and Immunology (B.C.M.), and Department of Cancer Biology and Department of Pharmacology, Vanderbilt University, Nashville, Tennessee (J.W.); Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio (M.S., J.D.L.); Department of Neuroscience and Pharmacology, Meharry Medical College, Nashville, Tennessee (S.L.); Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (J.N.S.).
authors.forename: Maksim
authors.initials: M
authors.lastname: Sinyuk
authors.affiliation: Department of Neurological Surgery (Y.G., Y.M., R.C.T., S.W.C., J.W.), Department of Molecular Physiology and Biophysics (W.C.), Department of Neurology (S.W.C.), Department of Pathology, Microbiology and Immunology (B.C.M.), and Department of Cancer Biology and Department of Pharmacology, Vanderbilt University, Nashville, Tennessee (J.W.); Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio (M.S., J.D.L.); Department of Neuroscience and Pharmacology, Meharry Medical College, Nashville, Tennessee (S.L.); Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (J.N.S.).
authors.forename: Sudan
authors.initials: S
authors.lastname: Loganathan
authors.affiliation: Department of Neurological Surgery (Y.G., Y.M., R.C.T., S.W.C., J.W.), Department of Molecular Physiology and Biophysics (W.C.), Department of Neurology (S.W.C.), Department of Pathology, Microbiology and Immunology (B.C.M.), and Department of Cancer Biology and Department of Pharmacology, Vanderbilt University, Nashville, Tennessee (J.W.); Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio (M.S., J.D.L.); Department of Neuroscience and Pharmacology, Meharry Medical College, Nashville, Tennessee (S.L.); Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (J.N.S.).
authors.forename: Reid C
authors.initials: RC
authors.lastname: Thompson
authors.affiliation: Department of Neurological Surgery (Y.G., Y.M., R.C.T., S.W.C., J.W.), Department of Molecular Physiology and Biophysics (W.C.), Department of Neurology (S.W.C.), Department of Pathology, Microbiology and Immunology (B.C.M.), and Department of Cancer Biology and Department of Pharmacology, Vanderbilt University, Nashville, Tennessee (J.W.); Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio (M.S., J.D.L.); Department of Neuroscience and Pharmacology, Meharry Medical College, Nashville, Tennessee (S.L.); Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (J.N.S.).
authors.forename: Jann N
authors.initials: JN
authors.lastname: Sarkaria
authors.affiliation: Department of Neurological Surgery (Y.G., Y.M., R.C.T., S.W.C., J.W.), Department of Molecular Physiology and Biophysics (W.C.), Department of Neurology (S.W.C.), Department of Pathology, Microbiology and Immunology (B.C.M.), and Department of Cancer Biology and Department of Pharmacology, Vanderbilt University, Nashville, Tennessee (J.W.); Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio (M.S., J.D.L.); Department of Neuroscience and Pharmacology, Meharry Medical College, Nashville, Tennessee (S.L.); Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (J.N.S.).
authors.forename: Wenbiao
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Neurological Surgery (Y.G., Y.M., R.C.T., S.W.C., J.W.), Department of Molecular Physiology and Biophysics (W.C.), Department of Neurology (S.W.C.), Department of Pathology, Microbiology and Immunology (B.C.M.), and Department of Cancer Biology and Department of Pharmacology, Vanderbilt University, Nashville, Tennessee (J.W.); Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio (M.S., J.D.L.); Department of Neuroscience and Pharmacology, Meharry Medical College, Nashville, Tennessee (S.L.); Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (J.N.S.).
authors.forename: Justin D
authors.initials: JD
authors.lastname: Lathia
authors.affiliation: Department of Neurological Surgery (Y.G., Y.M., R.C.T., S.W.C., J.W.), Department of Molecular Physiology and Biophysics (W.C.), Department of Neurology (S.W.C.), Department of Pathology, Microbiology and Immunology (B.C.M.), and Department of Cancer Biology and Department of Pharmacology, Vanderbilt University, Nashville, Tennessee (J.W.); Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio (M.S., J.D.L.); Department of Neuroscience and Pharmacology, Meharry Medical College, Nashville, Tennessee (S.L.); Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (J.N.S.).
authors.forename: Bret C
authors.initials: BC
authors.lastname: Mobley
authors.affiliation: Department of Neurological Surgery (Y.G., Y.M., R.C.T., S.W.C., J.W.), Department of Molecular Physiology and Biophysics (W.C.), Department of Neurology (S.W.C.), Department of Pathology, Microbiology and Immunology (B.C.M.), and Department of Cancer Biology and Department of Pharmacology, Vanderbilt University, Nashville, Tennessee (J.W.); Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio (M.S., J.D.L.); Department of Neuroscience and Pharmacology, Meharry Medical College, Nashville, Tennessee (S.L.); Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (J.N.S.).
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Clark
authors.affiliation: Department of Neurological Surgery (Y.G., Y.M., R.C.T., S.W.C., J.W.), Department of Molecular Physiology and Biophysics (W.C.), Department of Neurology (S.W.C.), Department of Pathology, Microbiology and Immunology (B.C.M.), and Department of Cancer Biology and Department of Pharmacology, Vanderbilt University, Nashville, Tennessee (J.W.); Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio (M.S., J.D.L.); Department of Neuroscience and Pharmacology, Meharry Medical College, Nashville, Tennessee (S.L.); Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (J.N.S.).
authors.forename: Jialiang
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism*; D049109:Cell Proliferation; D002470:Cell Survival; D005260:Female; D005909:Glioblastoma / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000008:administration & dosage / Q000096:biosynthesis / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D008819:Mice, Nude; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin / Q000378:metabolism*; D017451:Receptors, Somatomedin / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D015703:Antigens, CD; C583557:IGF1 protein, human; C000597236:IGF1R protein, human; C035170:IGF2 protein, human; D007328:Insulin; D017451:Receptors, Somatomedin; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; C435941:INSR protein, human; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt; IGF1R; glioblastoma; insulin; insulin receptor