Differential effects of the Akt inhibitor MK-2206 on migration and radiation sensitivity of glioblastoma cells
Abstract 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 combinat...
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doaj-7e4c68ffa40347c499cac312a61477892020-11-25T02:23:05ZengBMCBMC Cancer1471-24072019-04-0119111810.1186/s12885-019-5517-4Differential effects of the Akt inhibitor MK-2206 on migration and radiation sensitivity of glioblastoma cellsCholpon S. Djuzenova0Vanessa Fiedler1Simon Memmel2Astrid Katzer3Dmitri Sisario4Philippa K. Brosch5Alexander Göhrung6Svenja Frister7Heiko Zimmermann8Michael Flentje9Vladimir L. Sukhorukov10Department of Radiation Oncology, University Hospital of WürzburgDepartment of Radiation Oncology, University Hospital of WürzburgDepartment of Radiation Oncology, University Hospital of WürzburgDepartment of Radiation Oncology, University Hospital of WürzburgDepartment of Biotechnology and Biophysics, University of WürzburgDepartment of Biotechnology and Biophysics, University of WürzburgDepartment of Radiation Oncology, University Hospital of WürzburgDepartment of Radiation Oncology, University Hospital of WürzburgFraunhofer-Institut für Biomedizinische TechnikDepartment of Radiation Oncology, University Hospital of WürzburgDepartment of Biotechnology and Biophysics, University of WürzburgAbstract 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.http://link.springer.com/article/10.1186/s12885-019-5517-4DNA damageGlioblastoma MultiformeHistone H2AXIrradiationMigrationmTOR |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
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 |
spellingShingle |
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 Differential effects of the Akt inhibitor MK-2206 on migration and radiation sensitivity of glioblastoma cells BMC Cancer DNA damage Glioblastoma Multiforme Histone H2AX Irradiation Migration mTOR |
author_facet |
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 |
author_sort |
Cholpon S. Djuzenova |
title |
Differential effects of the Akt inhibitor MK-2206 on migration and radiation sensitivity of glioblastoma cells |
title_short |
Differential effects of the Akt inhibitor MK-2206 on migration and radiation sensitivity of glioblastoma cells |
title_full |
Differential effects of the Akt inhibitor MK-2206 on migration and radiation sensitivity of glioblastoma cells |
title_fullStr |
Differential effects of the Akt inhibitor MK-2206 on migration and radiation sensitivity of glioblastoma cells |
title_full_unstemmed |
Differential effects of the Akt inhibitor MK-2206 on migration and radiation sensitivity of glioblastoma cells |
title_sort |
differential effects of the akt inhibitor mk-2206 on migration and radiation sensitivity of glioblastoma cells |
publisher |
BMC |
series |
BMC Cancer |
issn |
1471-2407 |
publishDate |
2019-04-01 |
description |
Abstract 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. |
topic |
DNA damage Glioblastoma Multiforme Histone H2AX Irradiation Migration mTOR |
url |
http://link.springer.com/article/10.1186/s12885-019-5517-4 |
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