Abstract |
Tumor suppressor gene PTEN is frequently mutated in a wide variety of cancers. However, the downstream targets or signal transduction pathways of PTEN remain not fully understood. By analyzing Pten-null mouse embryonic fibroblasts (MEFs) cell lines and their isogenic counterparts, we showed that loss of PTEN led to increased cyclooxygenase2 (COX2) expression in an AKT-independent manner. Moreover, we demonstrated that PTEN deficiency promotes the transcription of COX2 via upregulation of the transcription factor Krüppel-like factor 5 (KLF5). Knocked down the expression of COX2 suppressed proliferation, migration and tumoral growth of Pten-null cells. Further experiments revealed that COX2 enhanced Pten-null MEFs growth and migration through upregulation of NADPH oxidase 4 (NOX4). In addition, MK-2206, a specific inhibitor of AKT, in combination with celecoxib, a COX2 inhibitor, strongly inhibited Pten-deficient cell growth. We concluded that KLF5/COX2/NOX4 signaling pathway is critical for cell growth and migration caused by the loss of PTEN, and the combination of MK-2206 and celecoxib may be an effective new approach to treating PTEN deficiency related tumors.
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Authors | Liang Zhang, Yuncui Wu, Jing Wu, Meng Zhou, Dapeng Li, Xiaofeng Wan, Fuquan Jin, Yani Wang, Wei Lin, Xiaojun Zha, Yehai Liu |
Journal | Cellular signalling
(Cell Signal)
Vol. 75
Pg. 109767
(11 2020)
ISSN: 1873-3913 [Electronic] England |
PMID | 32890667
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2020 Elsevier Inc. All rights reserved. |
Chemical References |
- KLF5 protein, human
- Klf5 protein, mouse
- Kruppel-Like Transcription Factors
- Ptgs2 protein, mouse
- Cyclooxygenase 2
- PTEN Phosphohydrolase
- PTEN protein, human
- Pten protein, mouse
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Topics |
- Animals
- Cell Line
- Cell Transformation, Neoplastic
- Cyclooxygenase 2
(metabolism)
- Gene Expression Regulation, Neoplastic
- HEK293 Cells
- Humans
- Kruppel-Like Transcription Factors
(metabolism)
- Mice
- Mice, Inbred BALB C
- PTEN Phosphohydrolase
(metabolism)
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