Sortilin regulates progranulin action in castration-Resistant prostate cancer cells

Ryuta Tanimoto, Alaide Morcavallo, Mario Terracciano, Shi Qiong Xu, Manuela Stefanello, Simone Buraschi, Kuojung G. Lu, Demetrius H. Bagley, Leonard G. Gomella, Katia Scotlandi, Antonino Belfiore, Renato V. Iozzo, Andrea Morrione

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

The growth factor progranulin is as an important regulator of transformation in several cellular systems.Wehave 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 evels in castration-resistant PC3 and DU145 cells. Significantly, enhancing sortilin expression in PC3 andDU145cells 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.

Original languageEnglish
Pages (from-to)58-70
Number of pages13
JournalEndocrinology
Volume156
Issue number1
DOIs
Publication statusPublished - Jan 1 2015
Externally publishedYes

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Castration
Prostatic Neoplasms
Intercellular Signaling Peptides and Proteins
Growth
sortilin
Proto-Oncogene Proteins c-akt
Clathrin
Endosomes
Protein Transport
Endocytosis
Small Interfering RNA
Neurons

ASJC Scopus subject areas

  • Endocrinology
  • Medicine(all)

Cite this

Tanimoto, R., Morcavallo, A., Terracciano, M., Xu, S. Q., Stefanello, M., Buraschi, S., ... Morrione, A. (2015). Sortilin regulates progranulin action in castration-Resistant prostate cancer cells. Endocrinology, 156(1), 58-70. https://doi.org/10.1210/en.2014-1590

Sortilin regulates progranulin action in castration-Resistant prostate cancer cells. / Tanimoto, Ryuta; Morcavallo, Alaide; Terracciano, Mario; Xu, Shi Qiong; Stefanello, Manuela; Buraschi, Simone; Lu, Kuojung G.; Bagley, Demetrius H.; Gomella, Leonard G.; Scotlandi, Katia; Belfiore, Antonino; Iozzo, Renato V.; Morrione, Andrea.

In: Endocrinology, Vol. 156, No. 1, 01.01.2015, p. 58-70.

Research output: Contribution to journalArticle

Tanimoto, R, Morcavallo, A, Terracciano, M, Xu, SQ, Stefanello, M, Buraschi, S, Lu, KG, Bagley, DH, Gomella, LG, Scotlandi, K, Belfiore, A, Iozzo, RV & Morrione, A 2015, 'Sortilin regulates progranulin action in castration-Resistant prostate cancer cells', Endocrinology, vol. 156, no. 1, pp. 58-70. https://doi.org/10.1210/en.2014-1590
Tanimoto R, Morcavallo A, Terracciano M, Xu SQ, Stefanello M, Buraschi S et al. Sortilin regulates progranulin action in castration-Resistant prostate cancer cells. Endocrinology. 2015 Jan 1;156(1):58-70. https://doi.org/10.1210/en.2014-1590
Tanimoto, Ryuta ; Morcavallo, Alaide ; Terracciano, Mario ; Xu, Shi Qiong ; Stefanello, Manuela ; Buraschi, Simone ; Lu, Kuojung G. ; Bagley, Demetrius H. ; Gomella, Leonard G. ; Scotlandi, Katia ; Belfiore, Antonino ; Iozzo, Renato V. ; Morrione, Andrea. / Sortilin regulates progranulin action in castration-Resistant prostate cancer cells. In: Endocrinology. 2015 ; Vol. 156, No. 1. pp. 58-70.
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