Androgen drives early endosome vesicular trafficking machinery expression to alter Appl1 endosome and leptin signaling in prostate cancer

Prostate cancer is the most diagnosed cancer in men and remains a leading cause of cancer related mortality worldwide. A deeper understanding of the cellular and molecular mechanisms that drive prostate cancer progression is essential for improving patient management and identifying new therapeutic targets. Endosomes serve as central hubs for immune function, nutrient sensing, inflammation and signal transduction, and their dysregulation may be central to prostate cancer pathogenesis. Here, we have focused on the early endosome adaptor protein Appl1, investigating the mechanistic links to androgen and leptin biology/signaling that are recognized hallmarks of prostate cancer biology. Appl1 expression increased with Gleason grade in tissue samples from patients with prostate cancer and had an altered cellular location in malignant androgen sensitive prostate cancer cells. Androgen stimulation modulated the expression of endosomal trafficking machinery to alter the spatial temporal distribution and function of Appl1. Appl1 co-located with the leptin receptor, while knockdown of either APPL1 or the myosin motor MYO6 resulted in attenuated Akt signaling following leptin stimulation. Mass spectrometry analysis revealed serine 401 phosphorylation of Appl1 in malignant androgen insensitive PC-3 and non-malignant PNT1a cells, but not in malignant androgen sensitive LNCaP prostate cells. Our findings indicated that androgens alter Appl1 trafficking to increase leptin signaling, providing a potential mechanistic link between altered spatiotemporal endosome biology and prostate cancer disease progression.