Dynamic interplay between sortilin and syndecan-1 drives a metabolic switch during prostate cancer progression

Author:

Lazniewska Joanna1,Li Ka Lok1,Johnson Ian1,Sorvina Alexandra1,Logan Jessica1,Martini Carmela1,Moore Courtney1,Ung Ben1,Karageorgos Litsa1,Prabhakaran Sarita1,Heatlie Jessica1,Brooks Robert1,Hickey Shane1,Huzzell Chelsea1,Warnock Nicholas2,Ward Mark3,Mohammed Bashir3,Tewari Prerna3,Martin Cara3,O'Toole Sharon3,Edgerton Laura Bogue3,Bates Mark3,Moretti Paul2,Pitson Stuart2,Selemidis Stavros4,Butler Lisa5,O'Leary John3,Brooks Douglas1

Affiliation:

1. University of South Australia

2. University of South Australia and SA Pathology

3. Trinity College Dublin

4. RMIT University

5. University of Adelaide

Abstract

Abstract Prostate cancer (PCa) development and progression relies on the programming of glucose and lipid metabolism, and this involves alterations in androgen receptor expression and signalling. Defining the molecular mechanism that underpins this metabolic programming will have direct significance for patients with PCa who have a poor prognosis. Here we show that there is a dynamic balance between sortilin and syndecan-1, that reports on different metabolic phenotypes. Using tissue microarrays, we demonstrated by immunohistochemistry that sortilin was highly expressed in low-grade cancer, while syndecan-1 was upregulated in high-grade disease. Mechanistic studies in prostate cell lines (selected to match the biomarker phenotypes in tissue from PCa patients) revealed that in androgen-sensitive LNCaP cells, sortilin enhanced glucose metabolism by regulating GLUT1 and GLUT4, while binding progranulin and lipoprotein lipase (LPL) to limit lipid metabolism. In contrast, in androgen-insensitive PC3 cells, syndecan-1 was upregulated, interacted with LPL and colocalised with β3 integrin to promote lipid metabolism. In addition, androgen-deprived LNCaP cells had decreased expression of sortilin and reduced glucose-metabolism, but increased syndecan-1 expression, facilitating interactions with LPL and possibly β3 integrin. We report a hitherto unappreciated molecular mechanism for PCa, which has significance for disease progression and how androgen-deprivation therapy may promote castration-resistant PCa.

Publisher

Research Square Platform LLC

Reference51 articles.

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