TY  - JOUR
A1  - Djuzenova, Cholpon S.
A1  - Fiedler, Vanessa
A1  - Memmel, Simon
A1  - Katzer, Astrid
A1  - Sisario, Dmitri
A1  - Brosch, Philippa K.
A1  - Göhrung, Alexander
A1  - Frister, Svenja
A1  - Zimmermann, Heiko
A1  - Flentje, Michael
A1  - Sukhorukov, Vladimir L.
T1  - Differential effects of the Akt inhibitor MK-2206 on migration and radiation sensitivity of glioblastoma cells
JF  - BMC Cancer
N2  - 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.
KW  - DNA damage
KW  - glioblastoma multiforme
KW  - histone H2AX
KW  - irradiation
KW  - migration
KW  - mTOR
KW  - PTEN
KW  - p53
KW  - radiation sensitivity
KW  - wound healing
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200290
VL  - 19
ER  - 
TY  - JOUR
A1  - Brosch, Philippa K.
A1  - Korsa, Tessa
A1  - Taban, Danush
A1  - Eiring, Patrick
A1  - Hildebrand, Sascha
A1  - Neubauer, Julia
A1  - Zimmermann, Heiko
A1  - Sauer, Markus
A1  - Shirakashi, Ryo
A1  - Djuzenova, Cholpon S.
A1  - Sisario, Dmitri
A1  - Sukhorukov, Vladimir L.
T1  - Glucose and inositol transporters, SLC5A1 and SLC5A3, in glioblastoma cell migration
JF  - Cancers
N2  - (1) Background: The recurrence of glioblastoma multiforme (GBM) is mainly due to invasion of the surrounding brain tissue, where organic solutes, including glucose and inositol, are abundant. Invasive cell migration has been linked to the aberrant expression of transmembrane solute-linked carriers (SLC). Here, we explore the role of glucose (SLC5A1) and inositol transporters (SLC5A3) in GBM cell migration. (2) Methods: Using immunofluorescence microscopy, we visualized the subcellular localization of SLC5A1 and SLC5A3 in two highly motile human GBM cell lines. We also employed wound-healing assays to examine the effect of SLC inhibition on GBM cell migration and examined the chemotactic potential of inositol. (3) Results: While GBM cell migration was significantly increased by extracellular inositol and glucose, it was strongly impaired by SLC transporter inhibition. In the GBM cell monolayers, both SLCs were exclusively detected in the migrating cells at the monolayer edge. In single GBM cells, both transporters were primarily localized at the leading edge of the lamellipodium. Interestingly, in GBM cells migrating via blebbing, SLC5A1 and SLC5A3 were predominantly detected in nascent and mature blebs, respectively. (4) Conclusion: We provide several lines of evidence for the involvement of SLC5A1 and SLC5A3 in GBM cell migration, thereby complementing the migration-associated transportome. Our findings suggest that SLC inhibition is a promising approach to GBM treatment.
KW  - volume regulation
KW  - transportome
KW  - phlorizin
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297498
SN  - 2072-6694
VL  - 14
IS  - 23
ER  -