Dietary Phytochemicals in Zinc Homeostasis: A Strategy for Prostate Cancer Management

Abstract

Studies have suggested an important role of the trace element zinc (Zn) in prostate biology and functions. Zn has been shown to exist in very high concentrations in the healthy prostate and is important for several prostatic functions. In prostate cancer (PCa), Zn levels are significantly decreased and inversely correlated with disease progression. Ideally, restoration of adequate Zn levels in premalignant/malignant prostate cells could abort prostate malignancy. However, studies have shown that Zn supplementation is not an efficient way to significantly increase Zn concentrations in PCa. Based on a limited number of investigations, the reason for the lower levels of Zn in PCa is believed to be the dysregulation of Zn transporters (especially ZIP and ZnT family of proteins), metallothioneins (for storing and releasing Zn), and their regulators (e.g., Zn finger transcription factor RREB1). Interestingly, the level of Zn in cells has been shown to be modulated by naturally occurring dietary phytochemicals. In this review, we discussed the effect of selected phytochemicals (quercetin, resveratrol, epigallocatechin-3-gallate and curcumin) on Zn functioning and proposes that Zn in combination with specific dietary phytochemicals may lead to enhanced Zn bioaccumulation in the prostate, and therefore, may inhibit PCa.

Keywords: metallothioneins; natural agents; prostate malignancy; zinc transporters.

Figure 1

The role of Zn and associated signaling in PCa. The PCa can be progressed via androgen-dependent and independent signaling mechanisms. In the androgen-dependent pathway, testosterone hormone binds to the androgen receptor (AR), which leads to its dissociation from heat shock proteins (HSP) and enables its nuclear translocation and binding to the androgen response element (ARE) increasing the expression of growth and survival genes as well as PSA. In the androgen-independent mechanism, growth factor signaling, cytokines and glucocorticoid signaling activate cell proliferative pathways such as PI3K-AKT, NF-κB, and JAK-STAT, leading to an increase in expression of growth and survival genes as well as prostate-specific antigen (PSA) [17]. Interestingly, Zn is known to modulate AR and PSA [18] as well as other signaling molecules such as AKT [20] and NF-κB [21,22]. Thus, Zn modulating agents could be used in the prevention and/or treatment of PCa. DHT, dihydrotestosterone; T/ DHEA, testosterone/dehydroepiandrosterone.