AKT1-CREB stimulation of PDGFRα expression is pivotal for PTEN deficient tumor development
Open Access
- 10 February 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Disease
- Vol. 12 (2), 1-17
- https://doi.org/10.1038/s41419-021-03433-0
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 alpha (PDGFR alpha) 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 alpha expression via activation of the AKT1-CREB signaling cascade. CREB transactivated PDGFR alpha expression by direct binding of the promoter of the PDGFR alpha gene. Depletion of PDGFR alpha attenuated the tumorigenicity of Pten-null cells in nude mice. Moreover, the PI3K-AKT signaling pathway has been shown to positively correlate with PDGFR alpha expression in multiple cancers. Augmented PDGFR alpha 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 alpha signaling pathway contributes to the tumor growth induced by PTEN deficiency and should be targeted for cancer treatment.Keywords
Funding Information
- Natural Science Foundation of Anhui Province (1808085MH261)
- National Natural Science Foundation of China (81372475)
This publication has 49 references indexed in Scilit:
- Targeting the PDGF signaling pathway in tumor treatmentCell Communication and Signaling, 2013
- clusterProfiler: an R Package for Comparing Biological Themes Among Gene ClustersOMICS: A Journal of Integrative Biology, 2012
- Regulation of neuroblastoma differentiation by forkhead transcription factors FOXO1/3/4 through the receptor tyrosine kinase PDGFRAProceedings of the National Academy of Sciences, 2012
- An Activating Mutation of AKT2 and Human HypoglycemiaScience, 2011
- CREB Is a Novel Nuclear Target of PTEN PhosphataseCancer Research, 2011
- Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascadeJCI Insight, 2010
- CREB in the Pathophysiology of Cancer: Implications for Targeting Transcription Factors for Cancer TherapyClinical Cancer Research, 2009
- AKT/PKB Signaling: Navigating DownstreamCell, 2007
- PDGFRs are critical for PI3K/Akt activation and negatively regulated by mTORJCI Insight, 2007
- Life with a Single Isoform of Akt: Mice Lacking Akt2 and Akt3 Are Viable but Display Impaired Glucose Homeostasis and Growth DeficienciesMolecular and Cellular Biology, 2006