Abstract
The Ras/Raf/MEK/extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (mTOR) signaling pathways are aberrantly activated in many tumors, including highly proliferative glioblastomas, but how they are wired with the cell cycle remains imperfectly understood. Inhibitors of MEK/ERK and mTOR pathways are tested as anticancer agents. They are generally considered to induce a G(1) cell cycle arrest through down-regulation of D-type cyclins and up-regulation of p27(kip1). Here, we examined the effect of targeting mTOR by rapamycin and/or MEK by PD184352 in human glioblastoma cell lines. In combination, these drugs cooperatively and potently inhibited the G(1)-S transition and retinoblastoma protein phosphorylation. Their cooperation could not be explained by their partial and differential inhibitory effects on cyclin D1 or D3 but instead by their synergistic inhibition of the activating T172 phosphorylation of cyclin-dependent kinase (CDK) 4. This appeared independent of p27 and unrelated to weak modulations of the CDK-activating kinase activity. The T172 phosphorylation of CDK4 thus appears as a crucial node integrating the activity of both MEK/ERK and mTOR pathways. Combined inhibition of both pathways should be considered as a promising strategy for treatment of tumors harboring a deregulated CDK4 activity.
Highlights
The Ras/Raf/MEK/extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling pathways are aberrantly activated in many tumors including glioblastomas, leading to deregulation of various metabolic processes, including proliferation and cell cycle progression
In serum-stimulated T98G and other glioblastoma cell lines, inhibition of MEK1/2 by PD184352 resulted in a selective dose-dependent decrease of ERK1/2 phosphorylation, whereas rapamycin completely and selectively inhibited the phosphorylation of p70S6 kinase and S6 protein, reflecting mTORC1 activity (Fig. 1A; Supplementary Fig. S1)
The synergy of rapamycin and PD184352 on CDK4 activity could not be explained by their partial and differential inhibitory effects on cyclin D1 or D3 accumulation but instead by their cooperative inhibition of CDK4 T172 phosphorylation, which appears independent of p27 or modulation of CDK-activating kinase (CAK) activity
Summary
The Ras/Raf/MEK/extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (mTOR) signaling pathways are aberrantly activated in many tumors including glioblastomas, leading to deregulation of various metabolic processes, including proliferation and cell cycle progression. Inhibitors of these cascades are of great interest for cancer therapy and are, or have been, used in clinical trials [1,2,3,4,5]. Doi:10.1158/0008-5472.CAN-08-3260 dependent kinases (CDK) 4/6 and 2 [6] This inhibition of CDK4 activity is believed to result from down-regulation of D-type cyclins [7,8,9,10] and/or accumulation of the CDK inhibitor p27kip1 [11]
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