Abstract
BackgroundMost 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.MethodsUsing 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.ResultsWe 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.ConclusionsOur 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.
Highlights
Most tumor cells show aberrantly activated Akt which leads to increased cell survival and resistance to cancer radiotherapy
Effects of Akt, PI3K, and Mammalian target of rapamycin (mTOR)-inhibition on the migration of glioblastoma multiforme (GBM) cells We recently reported that the migration activity of SNB19 cells is much less responsive to PI3K/mTOR inhibition than that of DK-MG cells [25]
Because the Akt/mTOR pathway is recognized as a major pathway regulating autophagy [16], we studied the role of autophagy in the development of radiation resistance in MK-2206-treated cells, especially in case of the SNB19 cell line
Summary
Most tumor cells show aberrantly activated Akt which leads to increased cell survival and resistance to cancer radiotherapy. The frequent activation of the PI3K pathway in cancer cells and its crucial role in cell growth and survival has made it a promising target for pharmacologic intervention (for review, see [1]). Patients whose tumors expressed high levels of p-Akt had decreased survival outcomes and increased metastatic spread after standard chemoradiation [4]. For these reasons, Akt is considered a promising target for cancer therapy and inhibition of Akt alone or in combination with standard
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