Title: Bacterial protein azurin as a new therapeutic tool to treat poor prognosis breast cancer with overexpression of P-cadherin
Background: Azurin is a small protein from the bacterium Pseudomonas aeruginosa. In the last years, this protein has been studied as a new anti-cancer therapeutic agent, mainly due to its preferential entry in cancer cells. Invasion is a hallmark of cancer to which P-cadherin was found to play an important role for a subset of breast cancers, being a poor prognosis factor associated with increased migration and invasiveness (Albergaria et al., 2012).
Aims, Results and Discussion: In this work, we aimed at using azurin as a new therapeutic agent towards this specific subset of breast cancer. Using biochemical and functional assays, we observed that azurin specifically targets P-cadherin, decreasing its pro-invasive role. Also, we observed that azurin impairs an important signaling pathway associated to P-cadherin overexpression, mediated by FAK/Src phosphorylation (Bernardes et al., 2013). In a genome-wide expression analysis of azurin-treated cells, we concluded that azurin up-regulated the endocytic process, concomitantly with the decrease in the expression of cell surface receptors, and decreased adhesion to the Extracellular Matrix (ECM). These observations were confirmed by the decrease of integrin subunit receptors and a decrease in the ability to form mammospheres, an important parameter of cancer resistance to therapies. We also propose a model of action for azurin, based in our results and in literature regarding azurin action, in which azurin enters in cancer cells through caveolae, and dislodges growth factor receptors and other cell surface receptors, often overexpressed in cancer cells. This way, azurin attenuates different signaling pathways hyper activated in cancer.
Conclusion and Future Perspectives: This work highlights the possibility of developing therapies to P-cadherin positive breast cancers based in this bacterial protein.
Acknowledgments: Funding from FCT is acknowledged.
Albergaria A, Ribeiro AS, Vieira AF, Sousa B, Nobre AR, Seruca R, Schmitt F, Paredes J (2011). P-cadherin role in normal breast development and cancer. Int J Dev Biol ;55(7-9):811-22.
Bernardes N, Ribeiro AS, Mota B, Matos RG, Arraiano CM, Seruca R, Paredes J and Fialho AM. (2013) The bacterial protein azurin impairs invasion and FAK/Src signaling in P-cadherin-overexpressing breast cancer cell models. PLoS ONE 8(7): e69023. doi:10.1371/journal.pone.0069023
PhD Degree: Biotechnology
Year of conclusion: 2013
Institution: Instituto Superior Técnico, University of Lisbon
Supervisor: Doctor Arsénio do Carmos Sales Mendes Fialho (firstname.lastname@example.org)
Co-Supervisor: Doctor Joana Cancela de Amorim Falcão Paredes (email@example.com)