The
phosphoinositide 3-kinase (PI3-K)/Akt signaling pathway is important in the regulation of cell proliferation through its production of
phosphatidylinositol 3,4,5-triphosphate (PIP3). Activation of this pathway is frequently observed in human
cancers, including
non-small cell lung carcinoma. The PI3-K/Akt pathway is negatively regulated by the
dual-specificity phosphatase and
tensin homolog (
PTEN) protein. PTEN acts as a direct antagonist of PI3-K by dephosphorylating PIP3. Studies have shown that
PTEN phosphatase activity is inhibited by PREX2, a
guanine nucleotide exchanger factor (GEF). Multiple studies revealed that CELF2, an
RNA binding protein, cooperates synergistically with PTEN as a
tumor suppressor in multiple
cancers. However, the underlying mechanism as to how CELF2 enhances PTEN activity remains unclear. Here, we report that CELF2 interacts with PREX2 and reduces the association of PREX2 with PTEN. Consistent with this observation,
PTEN phosphatase activity is upregulated with CELF2 overexpression. In addition, overexpression of CELF2 represses both Akt phosphorylation and cell proliferation only in the presence of PTEN. In an ex vivo study, CELF2 gene delivery could significantly inhibit patient-derived xenografts (PDX)
tumor growth. To further investigate the clinical relevance of this finding, we analyzed 87 paired clinical
lung adenocarcinoma samples and the results showed that CELF2
protein expression is downregulated in
tumor tissues and associated with poor prognosis. The CELF2 gene is located on the chromosome 10p arm, a region frequently lost in human
cancers, including breast invasive
carcinoma, low-grade
glioma and
glioblastoma. Analysis of TCGA datasets showed that CELF2 expression is also associated with shorter patient survival time in all these
cancers. Overall, our work suggests that CELF2 plays a novel role in PI3-K signaling by antagonizing the oncogenic effect of PREX2.