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

Affiliation

Wan X(#)(1)(2), Zhou M(#)(1), Huang F(#)(3), Zhao N(3), Chen X(1), Wu Y(1), Zhu W(4), Ni Z(1), Jin F(1), Wang Y(1), Hu Z(5), Chen X(6), Ren M(4), Zhang H(7), Zha X(8).
Author information:
(1)Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China.
(2)Department of Laboratory, Cancer Hospital, Chinese Academy of Sciences, Hefei, China.
(3)State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
(4)Department of Breast Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
(5)Modern Research Center for Traditional Chinese Medicine, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China.
(6)Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
(7)State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. [Email]
(8)Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China. [Email]
(#)Contributed equally

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