The interplay between androgens and low density lipoprotein-cholesterol in modulating prostate cancer cell fate and metabolism
Background: Androgens, the known drivers of prostate cancer (PCa) growth, have been indicated as important metabolic regulators with a relevant role in stimulating lipid metabolism. Also, the relationship between obesity and the aggressiveness of PCa has been established. However, it is unknown if the hormonal environment may alter the response of PCa cells to lipid availability. The present study evaluated the effect of 5α-dihydrotestosterone (DHT) in regulating lipid metabolism, and the interplay between this hormone and low-density lipoprotein (LDL)-cholesterol in modulating PCa cells fate. Materials and methods: Non-neoplastic, and androgen-sensitive and castration-resistant PCa cells were treated with 10 nM DHT, and the expression of fatty acids transporter, fatty acid synthase (FASN), and carnitine palmitoyltransferase 1A (CPT1A) evaluated. PCa cells were also exposed to LDL (100 μg/ml) in the presence or absence of DHT. Results: Treatment with DHT upregulated the expression of FASN and CPT1A in androgen-sensitive PCa cells. In contrast, LDL supplementation suppressed FASN expression regardless of the presence of DHT, whereas augmenting CPT1A levels. Our results also showed that LDL-cholesterol increased PCa cells viability, proliferation, and migration dependently on the presence of DHT. Moreover, LDL and DHT synergistically enhanced the accumulation of lipid droplets in PCa cells. Conclusions: Overall, the obtained results show that androgens deregulate lipid metabolism and enhance the effects of LDL increasing PCa cells viability, proliferation and migration. The present findings support clinical data linking obesity with PCa and first implicate androgens in this relationship. The present study sustains the application of pharmacological approaches targeting cholesterol availability and androgens signaling simultaneously.