AKT1-CREB stimulation of PDGFR? expression is pivotal for PTEN deficient tumor development.

ABSTRACT: 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 ? (PDGFR?) 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? expression via activation of the AKT1-CREB signaling cascade. CREB transactivated PDGFR? expression by direct binding of the promoter of the PDGFR? gene. Depletion of PDGFR? attenuated the tumorigenicity of Pten-null cells in nude mice. Moreover, the PI3K-AKT signaling pathway has been shown to positively correlate with PDGFR? expression in multiple cancers. Augmented PDGFR? 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? signaling pathway contributes to the tumor growth induced by PTEN deficiency and should be targeted for cancer treatment.

SUBMITTER: Wan X 

PROVIDER: S-EPMC7876135 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature