Dynamic interplay between sortilin and syndecan-1 contributes to prostate cancer progression

Joanna Lazniewska, Ka Lok Li, Ian R.D. Johnson, Alexandra Sorvina, Jessica M. Logan, Carmela Martini, Courtney Moore, Ben S.Y. Ung, Litsa Karageorgos, Shane M. Hickey, Sarita Prabhakaran, Jessica K. Heatlie, Robert D. Brooks, Chelsea Huzzell, Nicholas I. Warnock, Mark P. Ward, Bashir Mohammed, Prerna Tewari, Cara Martin, Sharon O’TooleLaura Bogue Edgerton, Mark Bates, Paul Moretti, Stuart M. Pitson, Stavros Selemidis, Lisa M. Butler, John J. O’Leary, Douglas A. Brooks

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)
18 Downloads (Pure)

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 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 may have significance for disease progression and how androgen-deprivation therapy might promote castration-resistant PCa.

Original languageEnglish
Article number13489
Number of pages18
JournalScientific Reports
Volume13
Issue number1
DOIs
Publication statusPublished - 18 Aug 2023

Keywords

  • Cancer metabolism
  • Endosomes
  • Prostate cancer
  • Tumour biomarkers

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