Targeting PTEN Regulation by Post Translational Modifications

SIMPLE SUMMARY: Cancer cells accumulate genetic alterations that improve their proliferation, survival, and migration capabilities. One of the most frequently altered signaling nodes in human cancer is the PI3-kinase /PTEN pathway. Most therapeutic efforts thus far have focused on the inhibition of PI3-kinase; however, a high proportion of tumors present an impaired activation of PTEN. While in some cases this is due to PTEN loss or inactivating mutations, PTEN activity can also be modulated by post-transcriptional modifications (PTMs). In this review, we discuss how these different modifications affect PTEN activity, and propose strategies to modulate these PTMs as an alternative approach for therapeutic treatment of PTEN-dependent tumors possessing at least one wild-type allele. ABSTRACT: Phosphatidylinositol-3,4,5-triphosphate (PIP(3)) is a lipidic second messenger present at very low concentrations in resting normal cells. PIP(3) levels, though, increase quickly and transiently after growth factor addition, upon activation of phosphatidylinositol 3-kinase (PI3-kinase). PIP(3) is required for the activation of intracellular signaling pathways that induce cell proliferation, cell migration, and survival. Given the critical role of this second messenger for cellular responses, PIP(3) levels must be tightly regulated. The lipid phosphatase PTEN (phosphatase and tensin-homolog in chromosome 10) is the phosphatase responsible for PIP(3) dephosphorylation to PIP(2). PTEN tumor suppressor is frequently inactivated in endometrium and prostate carcinomas, and also in glioblastoma, illustrating the contribution of elevated PIP(3) levels for cancer development. PTEN biological activity can be modulated by heterozygous gene loss, gene mutation, and epigenetic or transcriptional alterations. In addition, PTEN can also be regulated by post-translational modifications. Acetylation, oxidation, phosphorylation, sumoylation, and ubiquitination can alter PTEN stability, cellular localization, or activity, highlighting the complexity of PTEN regulation. While current strategies to treat tumors exhibiting a deregulated PI3-kinase/PTEN axis have focused on PI3-kinase inhibition, a better understanding of PTEN post-translational modifications could provide new therapeutic strategies to restore PTEN action in PIP(3)-dependent tumors.