AKT1-CREB stimulation of PDGFRα 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 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.

RUNX1/EGFR pathway contributes to STAT3 activation and tumor growth caused by hyperactivated mTORC1

“…All MEFs, including Tsc1 +/+ , Tsc1 −/− , Tsc2 +/+ , Tsc2 −/− , Pten +/+ , Pten −/− , pLXIN or pLXIN-hTSC2 retrovirus-infected Tsc2 −/− MEFs, pLXIN or pLXIN-myrAKT1 retrovirus-infected Pten +/+ MEFs, rat uterine leiomyoma-derived Tsc2-null ELT3 cells, and NTC/T2-null cells have been described previously. 17 , 21 , 51 , 52 SKOV3, DU145, and HEK 293T cells were obtained from the ATCC (Manassas, VA, USA). ELT3 cells were maintained and propagated in DMEM/F12 (1:1) with 10% fetal bovine serum (FBS).…”

Motoneuron-Specific PTEN Deletion in Mice Induces Neuronal Hypertrophy and Also Regeneration after Facial Nerve Injury

“…9). Interestingly, this novel finding in neurons was corroborated in PTEN-deficient mouse embryonic fibroblasts (Wan et al, 2021). Furthermore, complementary to PTEN deletion, PTEN overexpression was associated with decreased CREB phosphorylation in the lung tissue of asthmatic mice (Wu et al, 2020).…”

STAT3/miR-130b-3p/MBNL1 feedback loop regulated by mTORC1 signaling promotes angiogenesis and tumor growth

“…All the mouse embryonic fibroblast (MEF) cell lines (including Tsc1 + / + , Tsc1 − / − , Tsc2 + / + , Tsc2 − / − , STAT3C-overexpressing Tsc2 + / + and the empty vector pBabe-transduced Tsc2 + / + MEFs) and NTC/T2 null (a cell line with potent tumorigenicity derived from a subcutaneous tumor formed by the injection of Tsc2 − / − MEFs in immunodeficient mice) cells have been described previously [ 20 – 22 ]. The HNSCC cell line FaDu, human umbilical vein endothelial cells (HUVECs), and HEK 293 T cells were obtained from the ATCC (VA, USA).…”