title: The role of AKT isoforms in glioblastoma: AKT3 delays tumor progression.
abstract: The growth factor receptor/PI3K/AKT pathway is an important drug target in many cancers including Glioblastoma. AKT, a key node in the pathway, has 3 isoforms, AKT1, AKT2 and AKT3. Here we investigate their role in GBM. We find each activated, ser473 phosphorylated isoform is present in some GBMs but expression patterns vary. There is a direct relationship between human GBM patient outcome and both AKT1 and AKT2 mRNA levels, but an inverse relationship with AKT3 mRNA. Furthermore, AKT3 mRNA levels were high in a less aggressive GBM subtype. Overexpressing AKT3 improves survival in a rodent model of GBM and decreases colony forming efficiency, but not growth rate, in glioma cells. Silencing AKT3 slows cell cycle progression in one cell line and increases apoptosis in another. Our studies of AKT3 substrates indicate (1) silencing both AKT2 and AKT3 reduces GSK3 phosphorylation (2) only AKT2 silencing reduces S6 phosphorylation. Since S6 phosphorylation is a marker of mTORC1 activity this indicates that AKT2 activates mTORC1, but AKT3 does not. Our results indicate AKT isoforms have different roles and downstream substrates in GBM. Unexpectedly, they indicate AKT3 delays tumor progression. Therefore strategies that inhibit AKT3 may be unhelpful in some GBM patients.
authors.affiliation: St. Josephs Hospital and Medical Center, Downtown campus, 445 N 5th Street, Suite 110, Phoenix, AZ, 85004, USA. a_joy@cox.net.|, 318 E Kaler, Phoenix, AZ, 85020, USA. a_joy@cox.net.
authors.forename: Anna
authors.identifier: 0000-0002-4452-2957
authors.initials: A
authors.lastname: Joy
authors.affiliation: St. Josephs Hospital and Medical Center, Downtown campus, 445 N 5th Street, Suite 110, Phoenix, AZ, 85004, USA.
authors.forename: Manisha
authors.initials: M
authors.lastname: Kapoor
authors.affiliation: St. Josephs Hospital and Medical Center, Downtown campus, 445 N 5th Street, Suite 110, Phoenix, AZ, 85004, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Georges
authors.affiliation: St. Josephs Hospital and Medical Center, Downtown campus, 445 N 5th Street, Suite 110, Phoenix, AZ, 85004, USA.
authors.forename: Lacy
authors.initials: L
authors.lastname: Butler
authors.affiliation: St. Josephs Hospital and Medical Center, Downtown campus, 445 N 5th Street, Suite 110, Phoenix, AZ, 85004, USA.
authors.forename: Yongchang
authors.initials: Y
authors.lastname: Chang
authors.affiliation: St. Josephs Hospital and Medical Center, Downtown campus, 445 N 5th Street, Suite 110, Phoenix, AZ, 85004, USA.
authors.forename: Chaokun
authors.initials: C
authors.lastname: Li
authors.affiliation: St. Josephs Hospital and Medical Center, Downtown campus, 445 N 5th Street, Suite 110, Phoenix, AZ, 85004, USA.
authors.forename: Acacia
authors.initials: A
authors.lastname: Crouch
authors.affiliation: University of California at San Francisco, San Francisco, CA, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Smirnov
authors.affiliation: Department of Neurosurgery, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Mitsitoshi
authors.initials: M
authors.lastname: Nakada
authors.affiliation: St. Josephs Hospital and Medical Center, Downtown campus, 445 N 5th Street, Suite 110, Phoenix, AZ, 85004, USA.
authors.forename: James
authors.initials: J
authors.lastname: Hepler
authors.affiliation: St. Josephs Hospital and Medical Center, Downtown campus, 445 N 5th Street, Suite 110, Phoenix, AZ, 85004, USA.
authors.forename: Max
authors.initials: M
authors.lastname: Marty
authors.affiliation: Department of Neurology, University of Arizona College of Medicine, 550 E. Van Buren St, Phoenix, AZ, 85004, USA.
authors.forename: Burt G
authors.initials: BG
authors.lastname: Feuerstein
mesh_terms: D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D005909:Glioblastoma / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D010766:Phosphorylation; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013997:Time Factors; D014162:Transfection
chemical_list: D020033:Protein Isoforms; D034741:RNA, Small Interfering; D012694:Serine; C494918:AKT1 protein, human; C494921:AKT2 protein, human; C491754:AKT3 protein, human; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3
keywords: AKT; AKT1; AKT2; AKT3; GBM; Glioblastoma