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

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 & beta;(3) 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 & beta;(3) 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.

Automated summary

The development and progression of prostate cancer are closely related to the regulation of glucose and lipid metabolism, as well as alterations in androgen receptor expression and signaling. This study reveals a previously unrecognized molecular mechanism for prostate cancer, which involves the dynamic balance between sortilin and syndecan-1 and their impact on different metabolic phenotypes. In androgen-sensitive cells, sortilin enhances glucose metabolism while limiting lipid metabolism, whereas in androgen-insensitive cells, syndecan-1 promotes lipid metabolism. Additionally, androgen-deprived cells show decreased expression of sortilin and increased expression of syndecan-1, contributing to altered glucose and lipid metabolism. These findings have important implications for understanding disease progression and castration-resistant prostate cancer in the context of androgen-deprivation therapy.