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.
Keywords: COX2; Celecoxib; KLF5; MK-2206; PTEN.
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