PIK3CA silencing restores anoikis sensitivity in endothelial cells.

The development, differentiation, and homeostasis of adherent cells are regulated by interactions among cells, the extracellular matrix (ECM), and soluble factors. Loss of these contacts induces anoikis, a specific form of apoptosis. Tumor cells acquire resistance to anoikis, enabling them to survive without anchorage, invade the vascular system, and colonize distant organs in a process known as metastasis. Activation of the PI3K/Akt signaling pathway is the most common mechanism underlying the acquisition of anoikis resistance in cancer cells. The role of phosphoinositide 3-kinase (PI3K) in cancer is highlighted by the frequent mutation of the gene encoding the p110α catalytic subunit in the most common human cancers. In this study, we aimed to elucidate the role of PI3K (p110α catalytic subunit) in the acquisition of the anoikis-resistant phenotype and in the regulation of cellular characteristics directly related to tumorigenesis. To this end, we performed PIK3CA gene silencing in anoikis-resistant endothelial cells. Consequently, these cells exhibited a reversal of malignancy-associated traits, including morphological characteristics, anoikis resistance, clonogenic potential, proliferation rate, invasiveness, and adhesive capacity, resembling those of wild-type endothelial cells. Furthermore, we observed an increased rate of apoptosis, accompanied by changes in the expression of pro- and anti-apoptotic molecules, as well as increased caspase activation. In summary, our findings demonstrate that PIK3CA silencing reverses key features of the anoikis-resistant endothelial cell phenotype and provides new insights into the molecular mechanisms underlying anoikis resistance.