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Serum PSA, together with digital rectal examination and imaging of the prostate gland, have remained the gold standard in urological practices for the management of and intervention for prostate cancer. Based on these adopted practices, the limitations of serum PSA in identifying aggressive prostate cancer has led us to evaluate whether urinary PSA levels might have any clinical utility in prostate cancer diagnosis. Utilizing the Access Hybritech PSA assay, we evaluated a total of n = 437 urine specimens from post-DRE prostate cancer patients. In our initial cohort, PSA tests from a total of one hundred and forty-six (n = 146) urine specimens were obtained from patients with aggressive (Gleason Score ≥ 8, n = 76) and non-aggressive (Gleason Score = 6, n = 70) prostate cancer. A second cohort, with a larger set of n = 291 urine samples from patients with aggressive (GS ≥ 7, n = 168) and non-aggressive (GS = 6, n = 123) prostate cancer, was also utilized in our study. Our data demonstrated that patients with aggressive disease had lower levels of urinary PSA compared to the non-aggressive patients, while the serum PSA levels were higher in patients with aggressive prostate disease. The discordance between serum and urine PSA levels was further validated by immuno-histochemistry (IHC) assay in biopsied tumors and in metastatic lesions (n = 62). Our data demonstrated that aggressive prostate cancer was negatively correlated with the PSA in prostate cancer tissues, and, unlike serum PSA, urinary PSA might serve a better surrogate for capitulating tissue milieus to detect aggressive prostate cancer. We further explored the utility of urine PSA as a cancer biomarker, either alone and in combination with serum PSA, and their ratio (serum to urine PSA) to predict disease status. Comparing the AUCs for the urine and serum PSA alone, we found that urinary PSA had a higher predictive power (AUC= 0.732) in detecting aggressive disease. Furthermore, combining the ratios between serum to urine PSA with urine and serum assay enhanced the performance (AUC = 0.811) in predicting aggressive prostate disease. These studies support the role of urinary PSA in combination with serum for detecting aggressive prostate cancer.

The emergence of castration-resistance is one of the major challenges in the management of patients with advanced prostate cancer. Although the spectrum of systemic therapies that are available for use alongside androgen deprivation for treatment of castration-resistant prostate cancer (CRPC) is expanding, none of these regimens are curative. Therefore, it is imperative to apply systems approaches to identify and understand the mechanisms that contribute to the development of CRPC. Using comprehensive proteomic approaches, we show that a glycosylation-related enzyme, alpha (1,6) fucosyltransferase (FUT8), which is upregulated in CRPC, might be responsible for resistance to androgen deprivation. Mechanistically, we demonstrated that overexpression of FUT8 resulted in upregulation of the cell surface epidermal growth factor receptor (EGFR) and corresponding downstream signaling, leading to increased cell survival in androgen-depleted conditions. We studied the coregulatory mechanisms of EGFR and FUT8 expression in CRPC xenograft models and found that castration induced FUT8 overexpression associated with increased expression of EGFR. Taken together, our findings suggest a crucial role played by FUT8 as a mediator in switching prostate cancer cells from nuclear receptor signaling (androgen receptor) to the cell surface receptor (EGFR) mechanisms in escaping castration-induced cell death. These findings have clinical implication in understanding the role of FUT8 as a master regulator of cell surface receptors in cancer-resistant phenotypes.