Abstract
MK-2206 is an inhibitor of Akt activation. It has been investigated as an anticancer drug in clinical trials assessing the potential of pAkt targeting therapy. The purpose of this study was to identify conditions that increase the sensitivity of cancer cells to MK-2206. We found that the treatment of cancer cells with a high concentration of salinomycin (Sal) reduced total Akt protein levels but increased activated Akt levels. When cancer cells were cotreated with MK-2206 and Sal, both pAkt and total Akt levels were reduced. Using microscopic observation, an assessment of cleaved PARP, FACS analysis of pre-G1 region, and Hoechst staining, we found that Sal increased apoptosis of MK-2206-treated cancer cells. These results suggest that cotreatment with MK-2206 and Sal sensitizes cancer cells via reduction of both pAkt and total Akt. Furthermore, cotreatment of cancer cells with Sal and MK-2206 reduced pp70S6K, pmTOR, and pPDK1 levels. In addition, Sal-induced activation of GSK3β, TSC2, and 4EBP1 was abolished by MK-2206 cotreatment. These results suggest that cotreatment using MK-2206 and Sal could be used as a therapeutic method to sensitize cancer cells through targeting of the PI3K/Akt/mTOR pathway. Our findings may contribute to the development of MK-2206-based sensitization therapies for cancer patients.
Highlights
MK-2206, an oral small molecule and allosteric Akt inhibitor, binds to the Akt protein through a site located in the pleckstrin-homology domain
MK-2206 is a first-in-class highly selective inhibitor of all Akt isoforms, which is active in several human cancer models through a number of possible mechanisms, including the induction of autophagy and apoptosis in glioma cells [1,2,3,4,5]
The effect of MK-2206 and Sal cotreatment on pAkt and total Akt was tested in Hs578T breast cancer cells
Summary
MK-2206, an oral small molecule and allosteric Akt inhibitor, binds to the Akt protein through a site located in the pleckstrin-homology domain. The binding of MK-2206 induces a conformational change of Akt that prevents its localization to the plasma membrane, inhibiting its subsequent activation [1,2,3,4,5]. MK-2206 is a first-in-class highly selective inhibitor of all Akt isoforms, which is active in several human cancer models through a number of possible mechanisms, including the induction of autophagy and apoptosis in glioma cells [1,2,3,4,5]. The effect of MK-2206 against glioma cells has been confirmed in vitro [14]. A more complete understanding of the mechanisms governing MK-2206 sensitization is required to facilitate its therapeutic use in patients with cancer. Identifying the mechanism(s) underlying cell sensitization to MK-2206 would be an important step in the development of new treatment methods for pharmacological cancer
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