Lipid Uptake Is an Androgen-Enhanced Lipid Supply Pathway Associated with Prostate Cancer Disease Progression and Bone Metastasis

Abstract

De novo lipogenesis is a well-described androgen receptor (AR)-regulated metabolic pathway that supports prostate cancer tumor growth by providing fuel, membrane material, and steroid hormone precursor. In contrast, our current understanding of lipid supply from uptake of exogenous lipids and its regulation by AR is limited, and exogenous lipids may play a much more significant role in prostate cancer and disease progression than previously thought. By applying advanced automated quantitative fluorescence microscopy, we provide the most comprehensive functional analysis of lipid uptake in cancer cells to date and demonstrate that treatment of ARpositive prostate cancer cell lines with androgens results in significantly increased cellular uptake of fatty acids, cholesterol, and low-density lipoprotein particles. Consistent with a direct, regulatory role of AR in this process, androgenenhanced lipid uptake can be blocked by the AR-antagonist enzalutamide, but is independent of proliferation and cellcycle progression. This work for the first time comprehensively delineates the lipid transporter landscape in prostate cancer cell lines and patient samples by analysis of transcriptomics and proteomics data, including the plasma membrane proteome. We show that androgen exposure or deprivation regulates the expression of multiple lipid transporters in prostate cancer cell lines and tumor xenografts and that mRNA and protein expression of lipid transporters is enhanced in bone metastatic disease when compared with primary, localized prostate cancer. Our findings provide a strong rationale to investigate lipid uptake as a therapeutic cotarget in the fight against advanced prostate cancer in combination with inhibitors of lipogenesis to delay disease progression and metastasis. Implications: Prostate cancer exhibits metabolic plasticity in acquiring lipids from uptake and lipogenesis at different disease stages, indicating potential therapeutic benefit by cotargeting lipid supply.

Therapy-induced lipid uptake and remodeling underpin ferroptosis hypersensitivity in prostate cancer

“…Our previous longitudinal analysis of LNCaP tumor xenografts in a model of CRPC progression following castration showed that CRPC tumors contained significantly higher lipid levels than tumors resected from sham-castrated mice [33]. These lipids included essential fatty acid (FA) derivatives, indicating that development of CRPC is associated with enhanced uptake of exogenous, diet-derived lipids [16]. A detailed review of transcriptomic data from this study by gene set variation analysis (GSVA) revealed that castration caused a negative enrichment of pathways involved in lipogenesis, mitochondrial activity and oxidative phosphorylation in tumors at nadir of serum PSA levels compared to non-castrated tumor-bearing mice (intact, control).…”

“…Above results suggested major changes to lipid metabolism networks by Enz. Previous studies, including our own work, have demonstrated that androgens strongly enhance cellular lipid content of PCa cells through enhanced lipogenesis [37, 38] and lipid uptake [16] and that AR antagonists block these lipid supply pathways. To measure Enz-induced changes to the cellular content of neutral lipids, lipid droplets, phospholipids and free cholesterol, we used quantitative single cell imaging (qSCI) of two fluorescent lipophilic dyes, Nile Red and Filipin.…”

“…Only recently has attention been given to lipid uptake and to map the lipid transporter landscape in cancer cells [42, 63], including our own work in PCa [16]. The observed Enz-induced increase in protein expression of both LDLR and SCARB1 along with increased transcript levels of several other lipid transporters (Figs.…”

“…Furthermore, increased expression of several lipid transporters were also observed in bone metastasis of CRPC patients (Fig. S4B, [16]); however, whether this is indirectly caused by the lipid-rich environment present in adult bone tissue (high adiposity) or directly by ATTs remains to be shown.…”

The Potent and Selective AMPK Inhibitor BAY-3827 Shows Strong Efficacy in Androgen-Dependent Prostate Cancer Models

“…Rather, prostate cancer has a unique dependency on lipid metabolism for energy production, which has been linked to enhanced fatty acid uptake [50], intracrine steroid synthesis and de novo fatty acid synthesis [49,50]. Despite the fact that the expression of many enzymes involved in synthesis, uptake and oxidation of lipids is under androgen control [51,52] and often upregulated in prostate cancer patients [53,54], blockade of androgen signaling will eventually cease to be e cacious in prostate cancer patients, suggesting that novel therapeutic agents that address directly lipid metabolism may represent a novel therapeutic opportunity [55]. The present data show that blockade of lipid metabolism inside prostate tumor cells using the AMPK inhibitor BAY-3827 has the potential to inhibit proliferation and future studies will show how this translates into the clinical setting.…”