title: Different functions of AKT1 and AKT2 in molecular pathways, cell migration and metabolism in colon cancer cells.
abstract: AKT is a central protein in many cellular pathways such as cell survival, proliferation, glucose uptake, metabolism, angiogenesis, as well as radiation and drug response. The three isoforms of AKT (AKT1, AKT2 and AKT3) are proposed to have different physiological functions, properties and expression patterns in a cell type-dependent manner. As of yet, not much is known about the influence of the different AKT isoforms in the genome and their effects in the metabolism of colorectal cancer cells. In the present study, DLD-1 isogenic AKT1, AKT2 and AKT1/2 knockout colon cancer cell lines were used as a model system in conjunction with the parental cell line in order to further elucidate the differences between the AKT isoforms and how they are involved in various cellular pathways. This was done using genome wide expression analyses, metabolic profiling and cell migration assays. In conclusion, downregulation of genes in the cell adhesion, extracellular matrix and Notch-pathways and upregulation of apoptosis and metastasis inhibitory genes in the p53-pathway, confirm that the knockout of both AKT1 and AKT2 will attenuate metastasis and tumor cell growth. This was verified with a reduction in migration rate in the AKT1 KO and AKT2 KO and most explicitly in the AKT1/2 KO. Furthermore, the knockout of AKT1, AKT2 or both, resulted in a reduction in lactate and alanine, suggesting that the metabolism of carbohydrates and glutathione was impaired. This was further verified in gene expression analyses, showing downregulation of genes involved in glucose metabolism. Additionally, both AKT1 KO and AKT2 KO demonstrated an impaired fatty acid metabolism. However, genes were upregulated in the Wnt and cell proliferation pathways, which could oppose this effect. AKT inhibition should therefore be combined with other effectors to attain the best effect.
authors.affiliation: Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Uppsala University, SE-751 85 Uppsala, Sweden.
authors.forename: Sara
authors.initials: S
authors.lastname: Häggblad Sahlberg
authors.affiliation: Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Uppsala University, SE-751 85 Uppsala, Sweden.
authors.forename: Anja C
authors.initials: AC
authors.lastname: Mortensen
authors.affiliation: Division of Analytical Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, SE-751 23 Uppsala, Sweden.
authors.forename: Jakob
authors.initials: J
authors.lastname: Haglöf
authors.affiliation: Division of Analytical Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, SE-751 23 Uppsala, Sweden.
authors.forename: Mikael K R
authors.initials: MK
authors.lastname: Engskog
authors.affiliation: Division of Analytical Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, SE-751 23 Uppsala, Sweden.
authors.forename: Torbjörn
authors.initials: T
authors.lastname: Arvidsson
authors.affiliation: Division of Analytical Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, SE-751 23 Uppsala, Sweden.
authors.forename: Curt
authors.initials: C
authors.lastname: Pettersson
authors.affiliation: Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Uppsala University, SE-751 85 Uppsala, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Glimelius
authors.affiliation: Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Uppsala University, SE-751 85 Uppsala, Sweden.
authors.forename: Bo
authors.initials: B
authors.lastname: Stenerlöw
authors.affiliation: Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Uppsala University, SE-751 85 Uppsala, Sweden.
authors.forename: Marika
authors.initials: M
authors.lastname: Nestor
mesh_terms: D000409:Alanine / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005227:Fatty Acids / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D055786:Gene Knockout Techniques; D005947:Glucose / Q000378:metabolism; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D053858:Metabolic Networks and Pathways / Q000235:genetics; D009362:Neoplasm Metastasis; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
chemical_list: D005227:Fatty Acids; D019344:Lactic Acid; C494918:AKT1 protein, human; C494921:AKT2 protein, human; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose; D000409:Alanine