Tributyltin Protumorigenic Effects Targeting Prostate Cancer Cell Metabolism, Proliferation, Migration, and Invasion

Prostate cancer (PCa) is an endocrine-related cancer highly dependent on androgenic signaling. Beyond hormone dependence, extrinsic factors play a significant role in the risk of developing PCa, which raises concern about the influence of environmental compounds such as endocrine-disrupting chemicals (EDCs). Tributyltin (TBT) is an EDC used in antifouling paints, and its androgenic (and obesogenic) actions have been described. This study investigated the effect of TBT on various cancer hallmarks, specifically its impact on the viability, metabolism, proliferation, migration, and invasion of prostate cells, using in vitro and in vivo models. Androgen-sensitive (LNCaP) and androgen-insensitive (PC3) PCa cells were exposed to 1-100 nM TBT for 24 and 48 h. Additionally, LNCaP cells were treated with 100 nM TBT in the presence of the androgen receptor antagonist bicalutamide (1-40 μM) or 10 nM TBT and/or low-density lipoprotein (LDL, 100 μg/mL) and 5α-dihydrotestosterone (DHT, 10 nM, 48 h). Wistar rats were administered TBT (50 μg/kg) every 3 days for 45 days. TBT disrupted glycolytic flux and lipid handling in prostate cells, enhancing their proliferative activity. Moreover, 100 nM TBT stimulated migration and invasion of LNCaP cells. Bicalutamide attenuated the effect of TBT in inducing glucose consumption and LNCaP cell proliferation. A 10× lower TBT concentration maintained the stimulatory effects on LNCaP cells' viability, proliferation, and migration/invasion, sustained by high LDL-cholesterol availability and DHT. Our results show TBT as a potential inducer of PCa progression and aggressiveness and contribute to increasing awareness about the roles of EDCs in the prostate carcinogenic process.