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.

• Authors: Xiaofeng Wan, Meng Zhou, Fuqiang Huang, Na Zhao, Xu Chen, Yuncui Wu, Wanhui Zhu, Zhaofei Ni, Fuquan Jin, Yani Wang, Zhongdong Hu, Xianguo Chen, Min Ren, Hongbing Zhang, Xiaojun Zha
• Journal: Cell death & disease (Cell Death Dis) Vol. 12 Issue 2 Pg. 172 (02 10 2021) ISSN: 2041-4889 [Electronic] England
• PMID: 33568640 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzimidazoles
• CP-673,451
• CREB1 protein, human
• Creb1 protein, mouse
• Cyclic AMP Response Element-Binding Protein
• Heterocyclic Compounds, 3-Ring
• MK 2206
• Protein Kinase Inhibitors
• Quinolines
• Receptor, Platelet-Derived Growth Factor alpha
• AKT1 protein, human
• Akt1 protein, mouse
• Proto-Oncogene Proteins c-akt
• PTEN Phosphohydrolase
• PTEN protein, human
• Pten protein, mouse

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Benzimidazoles (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cyclic AMP Response Element-Binding Protein (genetics, metabolism)
• Fibroblasts (drug effects, enzymology, pathology)
• Gene Expression Regulation, Neoplastic
• HEK293 Cells
• Heterocyclic Compounds, 3-Ring (pharmacology)
• Humans
• Liver (drug effects, enzymology, pathology)
• Male
• Mice, Inbred BALB C
• Mice, Knockout
• Mice, Nude
• Neoplasms (drug therapy, enzymology, genetics, pathology)
• PTEN Phosphohydrolase (deficiency, genetics)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, genetics, metabolism)
• Quinolines (pharmacology)
• Receptor, Platelet-Derived Growth Factor alpha (genetics, metabolism)
• Signal Transduction
• Xenograft Model Antitumor Assays