A novel role for drebrin in regulating progranulin bioactivity in bladder cancer

// Shi-Qiong Xu 1, * , Simone Buraschi 2, * , Alaide Morcavallo 1, 3 , Marco Genua 1 , Tomoaki Shirao 4 , Stephen C. Peiper 2 , Leonard G. Gomella 1 , Ruth Birbe 2 , Antonino Belfiore 3 , Renato V. Iozzo 2 , Andrea Morrione 1 1 Department of Urology and Biology of Prostate Cancer Program, Thomas Jefferson University, Philadelphia, PA, USA 2 Department of Pathology, Anatomy and Cell Biology and Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA 3 Department of Health and Endocrinology, University Magna Graecia of Catanzaro, Catanzaro, Italy 4 Department of Neurobiology and Behavior, Gunma University School of Medicine, Showamachi, Maebashi, Japan * These authors have contributed equally to this work Correspondence to: Andrea Morrione, e-mail: Andrea.Morrione@jefferson.edu Renato V. Iozzo, e-mail: renato.iozzo@jefferson.edu Keywords: Progranulin, drebrin, bladder cancer, migration, invasion and anchorage-independent growth Received: October 13, 2014      Accepted: February 23, 2015      Published: March 12, 2015 ABSTRACT We recently established a critical role for the growth factor progranulin in bladder cancer insofar as progranulin promotes urothelial cancer cell motility and contributes, as an autocrine growth factor, to the transformed phenotype by modulating invasion and anchorage-independent growth. In addition, progranulin expression is upregulated in invasive bladder cancer tissues compared to normal controls. However, the molecular mechanisms of progranulin action in bladder cancer have not been fully elucidated. In this study, we searched for novel progranulin-interacting proteins using pull-down assays with recombinant progranulin and proteomics. We discovered that drebrin, an F-actin binding protein, bound progranulin in urothelial cancer cells. We characterized drebrin function in urothelial cancer cell lines and showed that drebrin is critical for progranulin-dependent activation of the Akt and MAPK pathways and modulates motility, invasion and anchorage-independent growth. In addition, drebrin regulates tumor formation in vivo and its expression is upregulated in bladder cancer tissues compared to normal tissue controls. Our data are translationally relevant as indicate that drebrin exerts an essential functional role in the regulation of progranulin action and may constitute a novel target for therapeutic intervention in bladder tumors. In addition, drebrin may serve as novel biomarker for bladder cancer.