Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China.
Department of Laboratory, Cancer Hospital, Chinese Academy of Sciences, Hefei, China.
Cell Death Dis. 2021 Feb 10;12(2):172. doi: 10.1038/s41419-021-03433-0.
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.
PTEN-AKT1 信号通路在人类癌症中发挥着关键作用，这一点可以从 AKT1 功能获得性突变背景下 PTEN 功能丧失突变体的行为得到证明。本研究通过对 Pten-/- 小鼠胚胎成纤维细胞、人癌细胞系、Pten 条件性敲除小鼠的肝组织和人癌组织的研究表明，PTEN 缺失或 AKT1 激活增强了血小板衍生生长因子受体 α (PDGFRα) 的表达。AKT1-CREB 信号级联的激活导致了 PTEN 缺失增强 PDGFRα 表达。CREB 通过直接结合 PDGFRα 基因启动子转录激活 PDGFRα 表达。PDGFRα 的耗竭减弱了裸鼠中 Pten 缺失细胞的致瘤性。此外，在多种癌症中，PI3K-AKT 信号通路与 PDGFRα 表达呈正相关。增强的 PDGFRα与癌症患者的不良预后相关。最后，AKT 抑制剂 MK-2206 和 PDGFR 抑制剂 CP-673451 的联合治疗显示出协同的抗肿瘤作用。因此，AKT1-CREB-PDGFRα 信号通路的激活有助于由 PTEN 缺失引起的肿瘤生长，应该作为癌症治疗的靶点。
