The Molecular Effects of Sulforaphane and Capsaicin on Metabolism upon Androgen and Tip60 Activation of Androgen Receptor

Abstract

Androgen receptor (AR) stimulators, such as androgen and Tip60, play a pivotal role in prostatic carcinogenesis as androgen receptor signaling is critical for the growth and transformation of the prostate gland. Moreover, androgen and Tip60 promotes HIF-1α activation, involved in metabolic reprogramming by increasing glycolysis, a hallmark in cancer initiation and development. In this study we evaluated the effect of androgen and Tip60 stimulus in AR pathway activation and HIF-1α stabilization, in terms of proliferation and cell metabolism in androgen-sensitive LNCaP cells. The protective role of the bioactive compounds sulforaphane and capsaicin against the effect of these stimuli leading to pro-carcinogenic features was also addressed. Sulforaphane and capsaicin decreased nuclear AR, prostate specific antigen and Bcl-XL levels, and cell proliferation induced by androgen and Tip60 in LNCaP cells. These bioactive compounds prevented the increase in glycolysis, hexokinase and pyruvate kinase activity, and reduced HIF-1α stabilization induced by androgen and Tip60 in LNCaP cells. The protective role of sulforaphane and capsaicin on prostate cancer may rely on mechanisms involving the inhibition of Tip60, AR and HIF-1α effects.

Metabolic Roles of Androgen Receptor and Tip60 in Androgen-Dependent Prostate Cancer

“…Consistent with other cancer types, an increase in glucose uptake or transporter is also associated with elevated glycolytic activity and emerging evidence has established the significance of the AR in glycolysis [7,9,10]. This is demonstrated by the increase in extracellular acidification rate, an indicator of glycolytic activity, following androgen treatment in androgen-dependent LNCaP and VCaP cells [7,[29][30][31]. The VCaP cell line was established from metastatic bone cancer and has amplified expression of the wild-type AR [39,40].…”

“…In fact, in human biopsies of hormone refractory prostate cancer, an increase in Tip60 expression and nuclear accumulation was observed compared to benign prostate hyperplasia and primary prostate cancer, in which a more cytoplasmic distribution was detected [89]. Interestingly, although AR activation mediated by Tip60 is associated with the presence of androgen stimulus, AR activation could be induced even in the absence of androgens when Tip60 is highly overexpressed [23,31]. A recent study has further demonstrated that overexpression of Tip60 alone was sufficient to increase cell proliferation and glycolytic activity, most probably through the stabilization of HIF-1α in LNCaP cells [31].…”

“…Indeed, growing evidence indicates that numerous types of cancer cells do have functional mitochondria and that OXPHOS plays an important role in the survival of cancer cells [28]. Based on these new insights, several studies have explored the roles of the AR in glucose metabolism, including glycolysis, the TCA cycle and OXPHOS using in vitro models of androgen-sensitive prostate cancer [7,9,10,[29][30][31].…”

“…Interestingly, although AR activation mediated by Tip60 is associated with the presence of androgen stimulus, AR activation could be induced even in the absence of androgens when Tip60 is highly overexpressed [23,31]. A recent study has further demonstrated that overexpression of Tip60 alone was sufficient to increase cell proliferation and glycolytic activity, most probably through the stabilization of HIF-1α in LNCaP cells [31]. This suggests that an overexpression of Tip60 with increased nuclear localization contributes to AR activation in an androgen-independent manner, thus promoting the transition of an androgen-responsive stage to castrate-resistant prostate cancer.…”

Hemin Prevents Increased Glycolysis in Macrophages upon Activation: Protection by Microbiota-Derived Metabolites of Polyphenols

“…The melanoma cells A375 cells (ATCC ® CRL-1619™) were used in this study for the epidemiological relevance of this type of cancer, as melanoma accounts for the majority of skin cancer deaths and its incidence has risen faster than almost any other cancer [ 49 ]. A375 cells were infected with purified lentiviral particles for red fluorescence protein and expanded as we previously described [ 50 ].…”