title: Akt isoform specific effects in ovarian cancer progression.
abstract: Ovarian cancer remains a significant therapeutic problem and novel, effective therapies are needed. Akt is a serine-threonine kinase that is overexpressed in numerous cancers, including ovarian. Mammalian cells express three Akt isoforms which are encoded by distinct genes. Although there are several Akt inhibitors in clinical trials, most indiscriminately target all isoforms. Current in vitro data and animal knockout experiments suggest that the Akt isoforms may have divergent roles. In this paper, we determined the isoform-specific functions of Akt in ovarian cancer cell proliferation in vitro and in ovarian cancer progression in vivo. For in vitro experiments, murine and human ovarian cancer cells were treated with Akt inhibitors and cell viability was assessed. We used two different in vivo approaches to identify the roles of Akt isoforms in ovarian cancer progression and their influence on the primary tumor and tumor microenvironment. In one experiment, wild-type C57Bl6 mice were orthotopically injected with ID8 cells with stable knockdown of Akt isoforms. In a separate experiment, mice null for Akt 1-3 were orthotopically injected with WT ID8 cells (Figure 1). Our data show that inhibition of Akt1 significantly reduced ovarian cancer cell proliferation and inhibited tumor progression in vivo. Conversely, disruption of Akt2 increased tumor growth. Inhibition of Akt3 had an intermediate phenotype, but also increased growth of ovarian cancer cells. These data suggest that there is minimal redundancy between the Akt isoforms in ovarian cancer progression. These findings have important implications in the design of Akt inhibitors for the effective treatment of ovarian cancer.
authors.affiliation: Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada.
authors.forename: Nicolle M
authors.initials: NM
authors.lastname: Linnerth-Petrik
authors.affiliation: Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Santry
authors.affiliation: Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada.
authors.forename: Roger
authors.initials: R
authors.lastname: Moorehead
authors.affiliation: Center of Experimental Medicine, Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Jücker
authors.affiliation: Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Wootton
authors.affiliation: Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada.
authors.forename: Jim
authors.initials: J
authors.lastname: Petrik
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D011379:Prognosis; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D047368:Tumor Burden
chemical_list: D000970:Antineoplastic Agents; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt inhibitors; Akt isoforms; ovarian cancer; tumor development