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KLF5-mediated COX2 upregulation contributes to tumorigenesis driven by PTEN deficiency.

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.
AuthorsLiang Zhang, Yuncui Wu, Jing Wu, Meng Zhou, Dapeng Li, Xiaofeng Wan, Fuquan Jin, Yani Wang, Wei Lin, Xiaojun Zha, Yehai Liu
JournalCellular signalling (Cell Signal) Vol. 75 Pg. 109767 (11 2020) ISSN: 1873-3913 [Electronic] England
PMID32890667 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 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
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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