uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Different functions of AKT1 and AKT2 in molecular pathways, cell migration and metabolism in colon cancer cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
Show others and affiliations
2017 (English)In: International Journal of Oncology, ISSN 1019-6439, Vol. 50, no 1, 5-14 p.Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
2017. Vol. 50, no 1, 5-14 p.
Keyword [en]
Microarray, metabolism, cell migration AKT1, AKT2, AKT, PKB, gene expression, colon-cancer, DLD-1, metabolomics, CD44, CD133
National Category
Biochemistry and Molecular Biology
Research subject
Biomedical Radiation Science; Biology with specialization in Molecular Cell Biology; Biology with specialization in Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-222834DOI: 10.3892/ijo.2016.3771ISI: 000391419200001OAI: oai:DiVA.org:uu-222834DiVA: diva2:712373
Available from: 2014-04-14 Created: 2014-04-14 Last updated: 2017-12-05Bibliographically approved
In thesis
1. Colorectal cancer and radiation response: The role of EGFR, AKT and cancer stem cell markers
Open this publication in new window or tab >>Colorectal cancer and radiation response: The role of EGFR, AKT and cancer stem cell markers
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
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. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 94 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 999
Keyword
colorectal cancer, radiation, AKT, EGFR, cancer stem cells, CD133, CD44
National Category
Cell Biology Biochemistry and Molecular Biology
Research subject
Biomedical Radiation Science; Biology with specialization in Molecular Cell Biology
Identifiers
urn:nbn:se:uu:diva-222836 (URN)978-91-554-8951-9 (ISBN)
Public defence
2014-06-05, Rudbecksalen, Dag Hammarskjöldsväg 20A, Uppsala, 14:00 (English)
Opponent
Supervisors
Available from: 2014-05-15 Created: 2014-04-14 Last updated: 2014-08-15Bibliographically approved

Open Access in DiVA

fulltext(562 kB)165 downloads
File information
File name FULLTEXT01.pdfFile size 562 kBChecksum SHA-512
8ac28b123d22abc99bdb45b323f302c85d02c0927320753d36d5dbf3d0e8aaca1d520a71ab0af0c9312c46815ce35d4bf994641d1578ecd5eebf8527c09223e7
Type fulltextMimetype application/pdf

Other links

Publisher's full text

Authority records BETA

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

Search in DiVA

By author/editor
Häggblad Sahlberg, SaraMortensen, Anja C.Haglöf, JakobEngskog, Mikael K. R.Arvidsson, TorbjörnPettersson, CurtGlimelius, BengtStenerlöw, BoNestor, Marika
By organisation
Department of Immunology, Genetics and PathologyMedical Radiation ScienceAnalytical Pharmaceutical ChemistryExperimental and Clinical OncologyScience for Life Laboratory, SciLifeLab
In the same journal
International Journal of Oncology
Biochemistry and Molecular Biology

Search outside of DiVA

GoogleGoogle Scholar
Total: 165 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
urn-nbn

Altmetric score

doi
urn-nbn
Total: 843 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf