Abstract
Bladder cancer (BC) is one of the most common cancers in the United States with 56,390 estimated new cases and 11,170 estimated deaths in 2014. The majority of deaths is due to metastatic spread. Understanding the molecular mechanisms regulating bladder tumor cell invasion and progression toward metastases is essential for developing better therapies to treat bladder cancer patients.
The growth factor progranulin plays an important role in cell proliferation, wound healing and transformation. We have recently established a critical role for 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 various urothelial cancer cell lines and showed that drebrin is critical for progranulin-dependent activation of the Akt and MAPK pathways and modulates F-actin remodeling, 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.
This work was supported by the Benjamin Perkins Bladder Cancer Fund, National Institutes of Health Grants RO1 CA164462 (A.M., R.V.I.), and RO1 CA39481 and RO1 CA47282 (R.V.I.), Associazione Italiana per la Ricerca sul Cancro (AIRC) (grant n. 10625/12), AIRC project Calabria 2014 and Fondazione Cassa di Risparmio di Calabria e Lucania PON01_01078 (A.B.). Alaide Morcavallo was supported in part by Fondazione Diabete Ricerca.
Citation Format: Shi-Qiong Xu, Simone Buraschi, Alaide Morcavallo, Marco Genua, Tomoaki Shirao, Stephen C. Peiper, Leonard G. Gomella, Antonino Belfiore, Renato V. Iozzo, Andrea Morrione. A novel role for drebrin in regulating progranulin bioactivity in bladder cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4945. doi:10.1158/1538-7445.AM2015-4945
- ©2015 American Association for Cancer Research.
Volume 75, Issue 15 Supplement
