Figure 8

Proposed schematic summary of sortilin and syndecan-1 roles in PCa cell metabolism at different stages of progression. In androgen-sensitive cells sortilin is involved in regulation of GLUT1 and GLUT4 surface expression. Sortilin, GLUT1 and some elements of trafficking machinery are directly or indirectly upregulated by androgens (dihydrotestosterone; DHT, androgen receptor; AR). Sortilin also keeps the level of progranulin and LPL low by controlling their degradation. Androgen deprivation leads to a decrease in sortilin, GLUT1 and Rab4A expression and an increase in syndecan-1 expression. Syndecan-1 promotes trafficking of LPL to the plasma membrane, which facilitates fatty acids uptake. Syndecan-1 also interacts with α_Vβ₃ integrin, which activates proliferation, survival and invasion pathways. Androgen-insensitive PCa cells express low amounts of sortilin but high amounts of progranulin, which is released to the extracellular environment. Progranulin binds to sortilin leading to its internalisation and degradation. Aggressive PCa cells also overexpress syndecan-1, which stimulate LPL trafficking to the cell surface to enhance lipid utilisation. Cleavage of syndecan-1 by metalloproteinases exposes its α_Vβ₃ integrin binding site, which facilitates interaction between the two molecules to promote cell proliferation, survival and invasion.