Abstract
BACKGROUND
Glioblastoma (GBM), the most lethal type of malignant brain cancer in adults, sustains frequent mutations and/or deletions in the tumor suppressor gene PTEN (phosphatase and tensin homolog), resulting in the activation of downstream mTOR-S6K signaling.
METHODS
We proposed experiments to test the hypothesis that PTEN deficiency induces signaling through both S6K1 and S6K2. We used for genome editing by knock down of S6K paralogs in combination with LY2584702, an S6K1 inhibitor.
RESULTS
We found that LY2584702 is highly specific for S6K1 inhibition in a kinome-wide analysis. Consistent with this result, gene-targeted S6K1-deficient cells exhibited little additive effect when treated LY2584702. S6K2 knockout induced a substantial reduction in the phosphorylation of the S6K substrate, ribosomal protein S6 (rpS6). Addition of LY2584702 reduced rpS6 phosphorylation further, indicating that S6K2 cooperates with S6K1 to mediate pathway signaling downstream of mTORC1 in PTEN-deficient glioma cells. Similar results employing genetic S6K1/S6K2 targeting using combination siRNA and sgRNA approaches are consistent with the results of LY2584702 experiments. We survey additional S6K substrates to define the relative contributions of S6K paralogs in signaling induced by PTEN-deficiency.
CONCLUSIONS
In short, our data support overlapping features of S6K1 and S6K2 regulation by PTEN, suggesting the importance of both kinases as clinical targets in GBM.