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Different functions of AKT1 and AKT2 in molecular pathways, cell migration and metabolism in colon cancer cells
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
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2017 (Engelska)Ingår i: International Journal of Oncology, ISSN 1019-6439, Vol. 50, nr 1, s. 5-14Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

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 AKT'/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.

Ort, förlag, år, upplaga, sidor
2017. Vol. 50, nr 1, s. 5-14
Nyckelord [en]
Microarray, metabolism, cell migration AKT1, AKT2, AKT, PKB, gene expression, colon-cancer, DLD-1, metabolomics, CD44, CD133
Nationell ämneskategori
Biokemi och molekylärbiologi
Forskningsämne
Biomedicinsk strålningsvetenskap; Biologi med inriktning mot molekylär cellbiologi; Biologi med inriktning mot molekylärbiologi
Identifikatorer
URN: urn:nbn:se:uu:diva-222834DOI: 10.3892/ijo.2016.3771ISI: 000391419200001OAI: oai:DiVA.org:uu-222834DiVA, id: diva2:712373
Tillgänglig från: 2014-04-14 Skapad: 2014-04-14 Senast uppdaterad: 2017-12-05Bibliografiskt granskad
Ingår i avhandling
1. Colorectal cancer and radiation response: The role of EGFR, AKT and cancer stem cell markers
Öppna denna publikation i ny flik eller fönster >>Colorectal cancer and radiation response: The role of EGFR, AKT and cancer stem cell markers
2014 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

The primary treatment for colorectal cancer is surgery. Radiotherapy and chemotherapy, sometimes combined, are also frequently used to diminish recurrence risk. In response to radiation exposure, several cellular signaling cascades are activated to repair DNA breaks, prevent apoptosis and to keep the cells proliferating. Several proteins in the radiation response and cell survival pathways are potential targets to enhance the effects of radiation. The epidermal growth factor receptor (EGFR), which is frequently upregulated in colorectal cancer and exhibits a radiation protective function, is an attractive target for treatment. EGFR is activated by radiation which in turn activates numerous signaling pathways such as the PI3 kinase/AKT cascade, the RAS/RAF/ERK pathway and STAT leading to tumor cell proliferation. EGFR is also believed to interact with proteins in the DNA repair process, such as DNA-PKcs and MRE11. The cytotoxic effect of an affibody molecule (ZEGFR:1907)2, with high affinity to EGFR,  in combination with radiation produced a small, but significant, reduction in survival in a KRAS mutated cell line. However, not in the BRAF mutated cell line. The next step was therefore to target proteins downstream of EGFR such as AKT. There was an interaction between AKT and the DNA repair proteins DNA-PKcs and MRE11 and both AKT1 and AKT2 were involved in the radiation response. The knockout of both AKT isoforms impaired the DNA double strand break rejoining after radiation and suppression of DNA-PKcs increased the radiations sensitivity and decreased the DNA repair further. The AKT isoforms also affected the expression of cancer stem cell markers CD133 and CD44 which are associated with the formation of metastasis as well as radiation and drug resistance. The CD133 expression was associated with AKT1 but not AKT2, whereas the CD44 expression was influenced by the presence of either AKT1 or AKT2. AKT was also involved in cell migration, cell-adhesion and metabolism. Overall, these results illustrate the complexity in response to radiation and drugs in cells with different mutations and the need for combining inhibitors against several targets such as EGFR, AKT, DNA-PKcs, CD133 or CD44. 

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2014. s. 94
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 999
Nyckelord
colorectal cancer, radiation, AKT, EGFR, cancer stem cells, CD133, CD44
Nationell ämneskategori
Cellbiologi Biokemi och molekylärbiologi
Forskningsämne
Biomedicinsk strålningsvetenskap; Biologi med inriktning mot molekylär cellbiologi
Identifikatorer
urn:nbn:se:uu:diva-222836 (URN)978-91-554-8951-9 (ISBN)
Disputation
2014-06-05, Rudbecksalen, Dag Hammarskjöldsväg 20A, Uppsala, 14:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2014-05-15 Skapad: 2014-04-14 Senast uppdaterad: 2014-08-15Bibliografiskt granskad

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Häggblad Sahlberg, SaraMortensen, Anja C.Haglöf, JakobEngskog, Mikael K. R.Arvidsson, TorbjörnPettersson, CurtGlimelius, BengtStenerlöw, BoNestor, Marika

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Häggblad Sahlberg, SaraMortensen, Anja C.Haglöf, JakobEngskog, Mikael K. R.Arvidsson, TorbjörnPettersson, CurtGlimelius, BengtStenerlöw, BoNestor, Marika
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Institutionen för immunologi, genetik och patologiMedicinsk strålningsvetenskapAvdelningen för analytisk farmaceutisk kemiExperimentell och klinisk onkologiScience for Life Laboratory, SciLifeLab
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