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.

肿瘤抑制基因PTEN在多种癌症中经常发生突变。然而，PTEN 的下游靶标或信号转导途径仍未完全了解。通过分析Pten 缺失的小鼠胚胎成纤维细胞 (MEF) 细胞系及其同基因对应物，我们发现 PTEN 的缺失导致环加氧酶 2 (COX2) 表达以 AKT 非依赖性方式增加。此外，我们证明 PTEN 缺乏通过转录因子 Krüppel 样因子 5（KLF5）的上调促进 COX2 的转录。敲低 COX2 的表达可抑制Pten- null 细胞的增殖、迁移和肿瘤生长。进一步的实验表明，COX2 增强了Pten- 通过上调 NADPH 氧化酶 4 (NOX4) 来抑制 MEF 的生长和迁移。此外，AKT 的特异性抑制剂 MK-2206 与 COX2 抑制剂塞来昔布联合使用，可强烈抑制Pten缺陷细胞的生长。我们得出结论，KLF5/COX2/NOX4 信号通路对 PTEN 缺失引起的细胞生长和迁移至关重要，MK-2206 和塞来昔布的组合可能是治疗 PTEN 缺乏相关肿瘤的有效新方法。