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

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 los...

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Veröffentlicht in:Cellular signalling 2020-11, Vol.75, p.109767-109767, Article 109767
Hauptverfasser: Zhang, Liang, Wu, Yuncui, Wu, Jing, Zhou, Meng, Li, Dapeng, Wan, Xiaofeng, Jin, Fuquan, Wang, Yani, Lin, Wei, Zha, Xiaojun, Liu, Yehai
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Sprache:eng
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Zusammenfassung: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. •Loss of PTEN upregulates COX2 in an AKT-independent manner.•PTEN deficiency promotes the expression of COX2 through upregulation of KLF5.•Depletion of COX2 suppresses PTEN deficiency-induced tumorigenesis.•COX2 increases the proliferative and migratory capacities of Pten-null cells via elevation of NOX4 expression.•Celecoxib in combination with MK-2206 plays a stronger inhibitory role on the growth of Pten-/- cells than either drug alone.
ISSN:0898-6568
1873-3913
DOI:10.1016/j.cellsig.2020.109767