Akt1-Creb Stimulation Of Pdgfr Alpha Expression Is Pivotal For Pten Deficient Tumor Development

As evidenced by the behavior of loss-of-function mutants of PTEN in the context of a gain-of-function mutation of AKT1, the PTEN-AKT1 signaling pathway plays a critical role in human cancers. In this study, we demonstrated that a deficiency in PTEN or activation of AKT1 potentiated the expression of platelet-derived growth factor receptor alpha (PDGFR alpha) based on studies on Pten-/- mouse embryonic fibroblasts, human cancer cell lines, the hepatic tissues of Pten conditional knockout mice, and human cancer tissues. Loss of PTEN enhanced PDGFR alpha expression via activation of the AKT1-CREB signaling cascade. CREB transactivated PDGFR alpha expression by direct binding of the promoter of the PDGFR alpha gene. Depletion of PDGFR alpha attenuated the tumorigenicity of Pten-null cells in nude mice. Moreover, the PI3K-AKT signaling pathway has been shown to positively correlate with PDGFR alpha expression in multiple cancers. Augmented PDGFR alpha was associated with poor survival of cancer patients. Lastly, combination treatment with the AKT inhibitor MK-2206 and the PDGFR inhibitor CP-673451 displayed synergistic anti-tumor effects. Therefore, activation of the AKT1-CREB-PDGFR alpha signaling pathway contributes to the tumor growth induced by PTEN deficiency and should be targeted for cancer treatment.