Abstract
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.
Highlights
Prostate cancer remains one of the most common malignancies in aging men and is the second leading cause of cancer related deaths in the USA [1]
Equal amounts of tryptic digested peptides were subjected to tandem mass tag (TMT) labeling followed by fractionation, and subsequent PTMs enrichment to facilitate global, phospho, and intact glycoproteomic (IGP) analysis as described in the Materials and Method Section
We evaluated the role of FUT8, a glycosylated related enzyme as a master regulator to be involved in the transformation of prostate cancer cells from nuclear receptor androgen receptor (AR)-dependent signaling to the cell surface including the epidermal growth factor receptor (EGFR) signaling
Summary
Prostate cancer remains one of the most common malignancies in aging men and is the second leading cause of cancer related deaths in the USA [1]. While the majority of men with prostate cancer will develop microscopic disease, only a few of these patients will develop aggressive prostate cancer [4]. Several mechanisms of resistance have been linked to the development of castration-resistant phenotypes including the gain of function mutations or amplification of the AR gene, the emergence of AR splice variants, overexpression of the AR cofactors, and ligand-independent activation of the AR by growth factors. In addition to these well-established mechanisms, alterations in post-translational modifications including glycosylation have been recently recognized in supporting cancer cells proliferation
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