title: Targeting aPKC disables oncogenic signaling by both the EGFR and the proinflammatory cytokine TNFα in glioblastoma.
abstract: Grade IV glioblastoma is characterized by increased kinase activity of epidermal growth factor receptor (EGFR); however, EGFR kinase inhibitors have failed to improve survival in individuals with this cancer because resistance to these drugs often develops. We showed that tumor necrosis factor-α (TNFα) produced in the glioblastoma microenvironment activated atypical protein kinase C (aPKC), thereby producing resistance to EGFR kinase inhibitors. Additionally, we identified that aPKC was required both for paracrine TNFα-dependent activation of the transcription factor nuclear factor κB (NF-κB) and for tumor cell-intrinsic receptor tyrosine kinase signaling. Targeting aPKC decreased tumor growth in mouse models of glioblastoma, including models of EGFR kinase inhibitor-resistant glioblastoma. Furthermore, aPKC abundance and activity were increased in human glioblastoma tumor cells, and high aPKC abundance correlated with poor prognosis. Thus, targeting aPKC might provide an improved molecular approach for glioblastoma therapy.
authors.affiliation: Neuroscience Graduate Program, Arizona State University, Phoenix, AZ 85287, USA.|Barrow Brain Tumor Research Center, Barrow Neurological Institute, Phoenix, AZ 85013, USA.
authors.forename: Yael
authors.initials: Y
authors.lastname: Kusne
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Eugenio A
authors.initials: EA
authors.lastname: Carrera-Silva
authors.affiliation: Department of Pathology, Banner MD Anderson Cancer Center, Gilbert, AZ 85234, USA.
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Perry
authors.affiliation: Armed Forces Institute of Pathology, Washington, DC 20306-0003, USA.
authors.forename: Elisabeth J
authors.initials: EJ
authors.lastname: Rushing
authors.affiliation: Department of Neurology, Yale University School of Medicine, New Haven, CT 06511, USA.
authors.forename: Edward K
authors.initials: EK
authors.lastname: Mandell
authors.affiliation: Bio5OV, The University of Arizona, Oro Valley, AZ 85737, USA.
authors.forename: Justin D
authors.initials: JD
authors.lastname: Dietrich
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Andrea E
authors.initials: AE
authors.lastname: Errasti
authors.affiliation: Department of Neurosciences, University of California, San Diego, San Diego, CA 92093, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gibbs
authors.affiliation: Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Berens
authors.affiliation: Mayo Clinic Arizona, Scottsdale, AZ 85259, USA.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Loftus
authors.affiliation: Bio5OV, The University of Arizona, Oro Valley, AZ 85737, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Hulme
authors.affiliation: MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Yang
authors.affiliation: MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Lu
authors.affiliation: MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Aldape
authors.affiliation: Neuroscience Graduate Program, Arizona State University, Phoenix, AZ 85287, USA.|Barrow Brain Tumor Research Center, Barrow Neurological Institute, Phoenix, AZ 85013, USA.
authors.forename: Nader
authors.initials: N
authors.lastname: Sanai
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Carla V
authors.initials: CV
authors.lastname: Rothlin
authors.affiliation: Neuroscience Graduate Program, Arizona State University, Phoenix, AZ 85287, USA.|Barrow Brain Tumor Research Center, Barrow Neurological Institute, Phoenix, AZ 85013, USA.|Department of Neurology, Yale University School of Medicine, New Haven, CT 06511, USA.|Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA.
authors.forename: Sourav
authors.initials: S
authors.lastname: Ghosh
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects / Q000378:metabolism*; D016503:Drug Delivery Systems; D004797:Enzyme-Linked Immunosorbent Assay; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005909:Glioblastoma / Q000188:drug therapy / Q000201:enzymology*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D053208:Kaplan-Meier Estimate; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D019899:Paracrine Communication / Q000502:physiology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D011799:Quinazolines; D014409:Tumor Necrosis Factor-alpha; D004815:Epidermal Growth Factor; D000069347:Erlotinib Hydrochloride; C541485:EGFR protein, mouse; D066246:ErbB Receptors; C115015:PKC-3 protein; D011493:Protein Kinase C