title: Sortilin regulates progranulin action in castration-resistant prostate cancer cells.
abstract: The growth factor progranulin is as an important regulator of transformation in several cellular systems. We have previously demonstrated that progranulin acts as an autocrine growth factor and stimulates motility, proliferation, and anchorage-independent growth of castration-resistant prostate cancer cells, supporting the hypothesis that progranulin may play a critical role in prostate cancer progression. However, the mechanisms regulating progranulin action in castration-resistant prostate cancer cells have not been characterized. Sortilin, a single-pass type I transmembrane protein of the vacuolar protein sorting 10 family, binds progranulin in neurons and negatively regulates progranulin signaling by mediating progranulin targeting for lysosomal degradation. However, whether sortilin is expressed in prostate cancer cells and plays any role in regulating progranulin action has not been established. Here, we show that sortilin is expressed at very low levels in castration-resistant PC3 and DU145 cells. Significantly, enhancing sortilin expression in PC3 and DU145 cells severely diminishes progranulin levels and inhibits motility, invasion, proliferation, and anchorage-independent growth. In addition, sortilin overexpression negatively modulates Akt (protein kinase B, PKB) stability. These results are recapitulated by depleting endogenous progranulin in PC3 and DU145 cells. On the contrary, targeting sortilin by short hairpin RNA approaches enhances progranulin levels and promotes motility, invasion, and anchorage-independent growth. We dissected the mechanisms of sortilin action and demonstrated that sortilin promotes progranulin endocytosis through a clathrin-dependent pathway, sorting into early endosomes and subsequent lysosomal degradation. Collectively, these results point out a critical role for sortilin in regulating progranulin action in castration-resistant prostate cancer cells, suggesting that sortilin loss may contribute to prostate cancer progression.
authors.affiliation: Departments of Urology (R.T., A.Morc., M.T., S.-Q.X., M.S., K.G.L., D.H.B., L.G.G., A.Morr.), Biology of Prostate Cancer Program (L.G.G., A.Morr.), and Pathology, Anatomy, and Cell Biology (S.B., R.V.I.) and Cancer Cell Biology and Signaling Program (R.V.I.), Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107; Department of Health Sciences (A.Morc., M.S., A.B.), Endocrinology, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy; and CRS Development of Biomolecular Therapies (M.T., K.S.), Experimental Oncology Laboratory, Rizzoli Orthopedic Institute, 40136 Bologna, Italy.
authors.forename: Ryuta
authors.initials: R
authors.lastname: Tanimoto
authors.forename: Alaide
authors.initials: A
authors.lastname: Morcavallo
authors.forename: Mario
authors.initials: M
authors.lastname: Terracciano
authors.forename: Shi-Qiong
authors.initials: SQ
authors.lastname: Xu
authors.forename: Manuela
authors.initials: M
authors.lastname: Stefanello
authors.forename: Simone
authors.initials: S
authors.lastname: Buraschi
authors.forename: Kuojung G
authors.initials: KG
authors.lastname: Lu
authors.forename: Demetrius H
authors.initials: DH
authors.lastname: Bagley
authors.forename: Leonard G
authors.initials: LG
authors.lastname: Gomella
authors.forename: Katia
authors.initials: K
authors.lastname: Scotlandi
authors.forename: Antonino
authors.initials: A
authors.lastname: Belfiore
authors.forename: Renato V
authors.initials: RV
authors.lastname: Iozzo
authors.forename: Andrea
authors.initials: A
authors.lastname: Morrione
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D000077153:Progranulins; D064129:Prostatic Neoplasms, Castration-Resistant / Q000378:metabolism*; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D000099183:Sortilin; C492314:GRN protein, human