A Small Molecule Inhibitor of PDK1/PLCγ 31 Interaction Blocks Breast and Melanoma Cancer Cell Invasion

Abstract

Strong evidence suggests that phospholipase Cγ 31 (PLCγ 31) is a suitable target to counteract tumourigenesis and metastasis dissemination. We recently identified a novel signalling pathway required for PLCγ 31 activation which involves formation of a protein complex with 3-phosphoinositide-dependent protein kinase 1 (PDK1). In an effort to define novel strategies to inhibit PLCγ 31-dependent signals we tested here whether a newly identified and highly specific PDK1 inhibitor, 2-O-benzyl-myo-inositol 1,3,4,5,6-pentakisphosphate (2-O-Bn-InsP 5), could affect PDK1/PLCγ 31 interaction and impair PLCγ 31-dependent cellular functions in cancer cells. Here, we demonstrate that 2-O-Bn-InsP 5 interacts specifically with the pleckstrin homology domain of PDK1 and impairs formation of a PDK1/PLCγ 31 complex. 2-O-Bn-InsP 5 is able to inhibit the epidermal growth factor-induced PLCγ 31 phosphorylation and activity, ultimately resulting in impaired cancer cell migration and invasion. Importantly, we report that 2-O-Bn-InsP 5 inhibits cancer cell dissemination in zebrafish xenotransplants. This work demonstrates that the PDK1/PLCγ 31 complex is a potential therapeutic target to prevent metastasis and it identifies 2-O-Bn-InsP 5 as a leading compound for development of anti-metastatic drugs.