Dynamic interplay between sortilin and syndecan-1 has a role in the metabolic switch during prostate cancer progression

Prostate cancer development and progression relies on the programming of glucose and lipid metabolism, and this involves alterations in androgen receptor expression and signalling. Androgen deprivation therapy (ADT) provides short-term efficacy for patient treatment, but inevitably promotes a castration-resistant phenotype with poor prognosis. Defining the molecular mechanism that underpins this metabolic programming will have direct significance for prostate cancer patients who have poor expected outcomes and/or receive ADT. Here we show that there is a dynamic balance between sortilin and syndecan-1 that reports on different metabolic phenotypes. Sortilin, enhances glucose metabolism by regulating GLUT1 and GLUT4, while binding progranulin and lipoprotein lipase (LPL) to limit lipid metabolism. In contrast, syndecan-1 interacts with LPL and ß3 integrin, to promote lipid metabolism and this process is upregulated in androgen-insensitive cells. We report a hitherto unappreciated molecular mechanism for prostate cancer, which has significance for disease progression and how ADT may promote castration-resistant prostate cancer. Overall design: Comparative gene expression profiling analysis of RNA-seq data for PC3 versus LNCaP cells and for LNCaP cells treated with dihydrotestosterone (DHT) vs vehicle (0.01% ethanol).