Mutant PIK3CA promotes cell growth and invasion of human cancer cells

Abstract

PIK3CA is mutated in diverse human cancers, but the functional effects of these mutations have not been defined. To evaluate the consequences of PIK3CA alterations, the two most common mutations were inactivated by gene targeting in colorectal cancer (CRC) cells. Biochemical analyses of these cells showed that mutant PIK3CA selectively regulated the phosphorylation of AKT and the forkhead transcription factors FKHR and FKHRL1. PIK3CA mutations had little effect on growth under standard conditions, but reduced cellular dependence on growth factors. PIK3CA mutations resulted in attenuation of apoptosis and facilitated tumor invasion. Treatment with the PI3K inhibitor LY294002 abrogated PIK3CA signaling and preferentially inhibited growth of PIK3CA mutant cells. These data have important implications for therapy of cancers harboring PIK3CA alterations.

Attenuation of the beta-catenin/TCF4 complex in colorectal cancer cells induces several growth-suppressive microRNAs that target cancer promoting genes

“…To experimentally address this issue, it will be necessary to evaluate whether a miR-30e-3p-resistant PIK3C2A construct stably expressed in DLD1 cells is able to rescue the growth-inhibitory phenotype imposed by miR-30e-3p. Most attention to PI3K signaling in CRC has been given to another PI3K variant, PIK3CA, because of its high mutation frequency also seen in other cancers, and it is worth noting that DLD1 cells (and HCT116) do in fact carry activating mutations in the PIK3CA gene (Samuels et al, 2005). Consequently, our results imply that PI3K isoforms do not act redundantly, and CRC cells remain sensitive to repressive signals acting on PIK3C2A, in this case illustrated by miR-30e-3p.…”

E-cadherin directly contributes to PI3K/AKT activation by engaging the PI3K-p85 regulatory subunit to adherens junctions of ovarian carcinoma cells

“…The PI3K pathway is genetically deregulated in human cancer at several levels (Samuels et al, 2005). Amplification of genomic regions and the somatic mutations of PIK3CA genes encoding the PI3K-p110 catalytic subunit have been reported and related to the activation of the PI3K pathway (Samuels et al, 2004).…”

Oncogenic E17K mutation in the pleckstrin homology domain of AKT1 promotes v-Abl-mediated pre-B-cell transformation and survival of Pim-deficient cells

“…The PI3K/AKT pathway is frequently activated in a variety of human cancers and is considered an attractive target for the development of novel chemotherapeutic agents. The activation of PI3K/AKT signaling in cancers is mainly due to loss of function of the tumor suppressor phosphatase and tensin homolog (PTEN) and activating mutations of PIK3CA gene, which encodes the p110 a-catalytic subunit of PI3K (Samuels et al, 2005;Manning and Cantley, 2007). The lipid kinase PIK3CA and the phosphatase PTEN exert their effect as regulators of AKT pathway by controlling the cellular levels of phosphatidylinositol-3,4,5-trisphosphate.…”