A Small Molecule Inhibitor of PDK1/PLCy1 Interaction Blocks Breast and Melanoma Cancer Cell Invasion.
MetadataShow full item record
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-phosphoinositidedependent 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-myoinositol 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.
Showing items related by title, author, creator and subject.
Overexpression of activated phospholipase C?1 is a risk factor for distant metastases in T1-T2, N0 breast cancer patients undergoing adjuvant chemotherapyLattanzio, R.; Marchisio, M.; La Sorda, R.; Tinari, N.; Falasca, Marco; Alberti, S.; Miscia, S.; Ercolani, C.; Di Benedetto, A.; Perracchio, L.; Melucci, E.; Iacobelli, S.; Mottolese, M.; Natali, P.; Piantelli, M. (2013)Phospholipase Cγ1 (PLCγ1) is highly expressed in several tumors. We have previously reported that both stable and inducible PLCγ1 down-regulation resulted in an almost complete inhibition of breast cancer-derived experimental ...
Emmanouilidi, A.; Lattanzio, R.; Sala, G.; Piantelli, M.; Falasca, Marco (2017)Breast cancer, the most common malignancy among women, is usually detected at an early stage and has a low risk of relapse. Nevertheless, a significant number of patients cannot be cured solely by local treatment. ...
Schaefer, Rainer (2008)At present, most cancers are treated with surgery, radiotherapy and chemotherapy, used alone or in combination. Surgery and radiotherapy are the primary treatment modalities after early detection of cancers and they ...