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

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.

• Authors: Shi-Qiong Xu, Simone Buraschi, Alaide Morcavallo, Marco Genua, Tomoaki Shirao, Stephen C Peiper, Leonard G Gomella, Ruth Birbe, Antonino Belfiore, Renato V Iozzo, Andrea Morrione
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 13 Pg. 10825-39 (May 10 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 25839164 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• GRN protein, human
• Intercellular Signaling Peptides and Proteins
• Neuropeptides
• Progranulins
• Rag2 protein, mouse
• drebrins
• Proto-Oncogene Proteins c-akt
• Mitogen-Activated Protein Kinases

Topics

• Actin Cytoskeleton (metabolism)
• Animals
• Cell Adhesion
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• DNA-Binding Proteins (deficiency, genetics)
• Gene Expression Regulation, Neoplastic
• Humans
• Intercellular Signaling Peptides and Proteins (genetics, metabolism)
• Mice, Knockout
• Mitogen-Activated Protein Kinases (metabolism)
• Neuropeptides (genetics, metabolism)
• Progranulins
• Protein Binding
• Proteomics (methods)
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA Interference
• Signal Transduction
• Transfection
• Urinary Bladder Neoplasms (genetics, metabolism, pathology)
• Urothelium (metabolism, pathology)