Obscurins were first described as cytoskeletal proteins with structural and regulatory roles, but recent studies have described this family of proteins to be involved in tumour and metastasis suppressing functions in normal breast epithelial cells. Furthermore, the loss of these proteins in the same tissue is correlated to physiological changes linked to tumour and metastatic behaviour. Here, giant obscurins are knocked-down in a human non-tumourigenic breast epithelial cell line to perform mechanistic studies. The results elucidated that the loss of giant obscurins induced the activation of PI3K and subsequent activation of AKT cascade. The inhibition of PI3K signalling pathway in the same conditions reversed the effect of the loss of giant obsucrins, inhibiting the transition towards cancerous cell behaviour. Finally, it was revealed that obsucrins are directly related to PI3K/p85 through the formation of complexes. Overall, the researchers use diverse methods coupled with gene expression modulation techniques to elucidate the role of giant obscurins in the prevention of tumour progression and propose a signalling pathway as the mechanistic explanation for it, pointing towards a new potential therapeutical target for metastasis prevention.
Giant obscurins regulate the PI3K cascade in breast epithelial cells via direct binding to the PI3K/p85 regulatory subunit
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