Molecular profiling of prostate cancer derived exosomes may reveal a predictive signature for response to docetaxel

// Pedram Kharaziha 1 , Dimitris Chioureas 1 , Dorothea Rutishauser 2, 3 , George Baltatzis 4 , Lena Lennartsson 1 , Pedro Fonseca 1 , Alireza Azimi 1 , Kjell Hultenby 5 , Roman Zubarev 2, 3 , Anders Ullen 1 , Jeffrey Yachnin 1 , Sten Nilsson 1 , Theocharis Panaretakis 1 1 Department of Oncology-Pathology, Karolinska Institutet and University Hospital, Stockholm, Sweden 2 Department of Medical Biochemistry and Biophysics, Karolinska Institutet and University Hospital, Stockholm, Sweden 3 Science for Life Laboratory, Stockholm, Sweden 4 Department of Medicine, School of Health Sciences, University of Athens, Athens, Greece 5 Department of Laboratory Medicine, Karolinska Institutet and University Hospital, Huddinge, Sweden Correspondence to: Theocharis Panaretakis, e-mail: theoharis.panaretakis@ki.se Keywords: Prostate cancer, exosomes, docetaxel, resistance, biomarkers Received: September 17, 2014      Accepted: January 27, 2015      Published: March 12, 2015 ABSTRACT Docetaxel is a cornerstone treatment for metastatic, castration resistant prostate cancer (CRPC) which remains a leading cause of cancer-related deaths, worldwide. The clinical usage of docetaxel has resulted in modest gains in survival, primarily due to the development of resistance. There are currently no clinical biomarkers available that predict whether a CRPC patient will respond or acquire resistance to this therapy. Comparative proteomics analysis of exosomes secreted from DU145 prostate cancer cells that are sensitive (DU145 Tax-Sen) or have acquired resistance (DU145 Tax-Res) to docetaxel, demonstrated significant differences in the amount of exosomes secreted and in their molecular composition. A panel of proteins was identified by proteomics to be differentially enriched in DU145 Tax-Res compared to DU145 Tax-Sen exosomes and was validated by western blotting. Importantly, we identified MDR-1, MDR-3, Endophilin-A2 and PABP4 that were enriched only in DU145 Tax-Res exosomes. We validated the presence of these proteins in the serum of a small cohort of patients. DU145 cells that have uptaken DU145 Tax-Res exosomes show properties of increased matrix degradation. In summary, exosomes derived from DU145 Tax-Res cells may be a valuable source of biomarkers for response to therapy.