Research Papers:

Proteomic analysis of zoledronic-acid resistant prostate cancer cells unveils novel pathways characterizing an invasive phenotype

Milone Maria Rita _, Pucci Biagio, Bifulco Katia, Iannelli Federica, Lombardi Rita, Chiara Ciardiello, Bruzzese Francesca, Carriero Maria Vincenza and Budillon Alfredo

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Oncotarget. 2015; 6:5324-5341. https://doi.org/10.18632/oncotarget.2694

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Maria Rita Milone1,*, Biagio Pucci1,*, Katia Bifulco3, Federica Iannelli1, Rita Lombardi1, Chiara Ciardiello2, Francesca Bruzzese2, Maria Vincenza Carriero3, Alfredo Budillon1,2

1Centro Ricerche Oncologiche Mercogliano, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, Naples, Italy

2Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, Naples, Italy

3Neoplastic Progression Unit, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, Naples, Italy

*These authors contributed equally to this work

Correspondence to:

Alfredo Budillon, e-mail: [email protected]

Keywords: prostate cancer, zoledronic acid, cytoskeleton organization, αv integrin, urokinase receptor (uPAR)

Received: July 25, 2014     Accepted: November 04, 2014     Published: November 24, 2014


Proteomic analysis identified differentially expressed proteins between zoledronic acid-resistant and aggressive DU145R80 prostate cancer (PCa) cells and their parental DU145 cells. Ingenuity Pathway Analysis (IPA) showed a strong relationship between the identified proteins within a network associated with cancer and with homogeneous cellular functions prevalently related with regulation of cell organization, movement and consistent with the smaller and reduced cell-cell contact morphology of DU145R80 cells. The identified proteins correlated in publically available human PCa genomic data with increased tumor expression and aggressiveness. DU145R80 exhibit also a clear increase of alpha-v-(αv) integrin, and of urokinase receptor (uPAR), both included within the same network of the identified proteins. Interestingly, the actin-rich structures localized at the cell periphery of DU145R80 cells are rich of Filamin A, one of the identified proteins and uPAR which, in turn, co-localizes with αv-integrin, in podosomes and/or invadopodia. Notably, the invasive feature of DU145R80 may be prevented by blocking anti-αv antibody. Overall, we unveil a signaling network that physically links the interior of the nucleus via the cytoskeleton to the extracellular matrix and that could dictate PCa aggressiveness suggesting novel potential prognostic markers and therapeutic targets for PCa patients.

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