Abstract
Strong evidence suggests that phospholipase Cγ1 (PLCγ1) is a suitable target to counteract tumourigenesis and metastasis dissemination. We recently identified a novel signalling pathway required for PLCγ1 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 PLCγ1-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-InsP5), could affect PDK1/PLCγ1 interaction and impair PLCγ1-dependent cellular functions in cancer cells. Here, we demonstrate that 2-O-Bn-InsP5 interacts specifically with the pleckstrin homology domain of PDK1 and impairs formation of a PDK1/PLCγ1 complex. 2-O-Bn-InsP5 is able to inhibit the epidermal growth factor-induced PLCγ1 phosphorylation and activity, ultimately resulting in impaired cancer cell migration and invasion. Importantly, we report that 2-O-Bn-InsP5 inhibits cancer cell dissemination in zebrafish xenotransplants. This work demonstrates that the PDK1/PLCγ1 complex is a potential therapeutic target to prevent metastasis and it identifies 2-O-Bn-InsP5 as a leading compound for development of anti-metastatic drugs.
Highlights
Metastasis, the ability of cancer cells to spread from a primary site and form tumours at distant sites, is the main cause of death in cancer patients[1]
Despite this evidence and further data indicating that phospholipase Cγ1 (PLCγ1) has a key role in tumourigenesis[3,6,12], the development of selective inhibitors has proven problematic since phospholipases in general are not very good pharmacological targets[6,23]
In our quest for inhibitors of PLCγ1 signalling we devised a strategy based on defining the signalling pathway and the interacting partners of phospholipase Cγ1 (PLCγ1) rather than targeting this phospholipase. This led us to the discovery for PDK1 as a novel PLCγ1 interacting protein[17] involved in the activation of the phospholipase and in the regulation of PLCγ1-dependent cellular functions, including cell invasion
Summary
Several lines of evidence from different groups including our own have indicated that inhibition of PLCγ1 may represent a promising strategy to block metastasis spread. We show that the 2-O-Bn-InsP5-mediated inhibition of PDK1/PLCγ1 complex assembly results in inhibition of cancer cell migration, invasion and in vivo dissemination using zebrafish xenotransplants (Fig. 6). Together these results strongly suggest that the blockade of PDK1/PLCγ1 interaction by. Our findings show that 2-O-Bn-InsP5 could lead to the development of distinct more selective ( less toxic) therapeutic strategies by targeting the PDK1/PLCγ1 complex formation at the plasma membrane and its downstream pathways that may lead to the development of novel drugs capable of selectively inhibiting the invasive potential of cancer cells
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