One in six men will be diagnosed with prostate cancer in their lifetime. Patients diagnosed with high-grade prostate cancer initially respond to treatment, however most patients eventually develop resistance to treatment and subsequently relapse with an incurable, castration-resistant disease. Thirty percent of these patients will go on to develop metastatic prostate cancer with a mean overall survival of less than two years. Metabolic reprogramming, a recognised hallmark of cancer, may contribute to this treatment resistance in metastatic prostate cancer.
Despite evidence of increased fatty acid uptake in prostate cancer, fatty acid oxidation rates and the contribution of extracellular fatty acids to citrate production are reduced. Furthermore, the preference for different lipid species, their subsequent localisation and fate has not been fully elucidated in prostate cancer. Using live-cell fluorescence microscopy and flow cytometry, we utilise fluorescently labelled medium- and long-chain fatty acids (C12:0 and C16:0, respectively) in the presence and absence of albumin to directly track uptake in non-malignant prostate cells (PNT1a), and androgen-dependent (LNCaP) and androgen-independent (PC3) prostate cancer cell lines. Despite the fact that most extracellular long-chain fatty acids require conjugation to albumin - a known fatty-acid transporter - to enter the cell, our results suggest an alternate uptake mechanism whereby significantly increased amounts of fatty acid can enter the cell in the absence of albumin. We also demonstrate a preference for C16:0 compared to C12:0 in PNT1a, LNCaP and PC3 cells, results that are consistent with other lipid-dependent malignanices such as chronic lymphocytic leukaemia. Imaging studies confirm varied fluorescence intensities and staining patterns of the fluorescently labelled fatty acids among cell lines, in the presence and absence of albumin.
We have preliminary evidence of different uptake mechanisms, and are currently testing the hypothesis that a dynamic process may operate to facilitate metastatic prostate cancer survival and propagation. We will use a variety of novel lipid droplet imaging agents and perform co-localisation experiments to identify mechanisms of fatty acid uptake and to track distribution and incorporation into prostate cancer cells. This research has the potential to unlock important lipid metabolic and cell biological dynamics that are critical drivers of metastatic prostate cancer.