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Differential effects of the Akt inhibitor MK-2206 on migration and radiation sensitivity of glioblastoma cells

Please always quote using this URN: urn:nbn:de:bvb:20-opus-200290
  • Background Most tumor cells show aberrantly activated Akt which leads to increased cell survival and resistance to cancer radiotherapy. Therefore, targeting Akt can be a promising strategy for radiosensitization. Here, we explore the impact of the Akt inhibitor MK-2206 alone and in combination with the dual PI3K and mTOR inhibitor PI-103 on the radiation sensitivity of glioblastoma cells. In addition, we examine migration of drug-treated cells. Methods Using single-cell tracking and wound healing migration tests, colony-forming assay,Background Most tumor cells show aberrantly activated Akt which leads to increased cell survival and resistance to cancer radiotherapy. Therefore, targeting Akt can be a promising strategy for radiosensitization. Here, we explore the impact of the Akt inhibitor MK-2206 alone and in combination with the dual PI3K and mTOR inhibitor PI-103 on the radiation sensitivity of glioblastoma cells. In addition, we examine migration of drug-treated cells. Methods Using single-cell tracking and wound healing migration tests, colony-forming assay, Western blotting, flow cytometry and electrorotation we examined the effects of MK-2206 and PI-103 and/or irradiation on the migration, radiation sensitivity, expression of several marker proteins, DNA damage, cell cycle progression and the plasma membrane properties in two glioblastoma (DK-MG and SNB19) cell lines, previously shown to differ markedly in their migratory behavior and response to PI3K/mTOR inhibition. Results We found that MK-2206 strongly reduces the migration of DK-MG but only moderately reduces the migration of SNB19 cells. Surprisingly, MK-2206 did not cause radiosensitization, but even increased colony-forming ability after irradiation. Moreover, MK-2206 did not enhance the radiosensitizing effect of PI-103. The results appear to contradict the strong depletion of p-Akt in MK-2206-treated cells. Possible reasons for the radioresistance of MK-2206-treated cells could be unaltered or in case of SNB19 cells even increased levels of p-mTOR and p-S6, as compared to the reduced expression of these proteins in PI-103-treated samples. We also found that MK-2206 did not enhance IR-induced DNA damage, neither did it cause cell cycle distortion, nor apoptosis nor excessive autophagy. Conclusions Our study provides proof that MK-2206 can effectively inhibit the expression of Akt in two glioblastoma cell lines. However, due to an aberrant activation of mTOR in response to Akt inhibition in PTEN mutated cells, the therapeutic window needs to be carefully defined, or a combination of Akt and mTOR inhibitors should be considered.show moreshow less

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Metadaten
Author: Cholpon S. Djuzenova, Vanessa Fiedler, Simon Memmel, Astrid Katzer, Dmitri Sisario, Philippa K. Brosch, Alexander Göhrung, Svenja Frister, Heiko Zimmermann, Michael Flentje, Vladimir L. Sukhorukov
URN:urn:nbn:de:bvb:20-opus-200290
Document Type:Journal article
Faculties:Medizinische Fakultät / Klinik und Poliklinik für Strahlentherapie
Fakultät für Biologie / Theodor-Boveri-Institut für Biowissenschaften
Language:English
Parent Title (English):BMC Cancer
Year of Completion:2019
Volume:19
Pagenumber:299
Source:BMC Cancer (2019) 19:299, https://doi.org/10.1186/s12885-019-5517-4
DOI:https://doi.org/10.1186/s12885-019-5517-4
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Tag:DNA damage; PTEN; glioblastoma multiforme; histone H2AX; irradiation; mTOR; migration; p53; radiation sensitivity; wound healing
Release Date:2020/03/11
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International