Jaboticaba peel extract limits castration-resistant prostate cancer aggressiveness by counteracting EMT through steroid hormone and TGF-β signaling modulation.

Androgen deprivation therapy (ADT) is recommended for treating prostate cancer (PCa) that relapses after first-line approaches. However, tumors often evolve to a highly aggressive and metastatic castration-resistant phenotype (CRPC). Epithelial-to-mesenchymal transition (EMT) stands out due to its contribution to hormone resistance and metastatic spread. We investigated the potential of a jaboticaba peel extract (JPE) as an adjuvant agent in CRPC tumors from the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model, focusing on EMT regulation. Sixteen-week-old mice underwent surgical and chemical castration (10 mg/Kg enzalutamide), alone or in combination with JPE (5.8 g/Kg). Control animals were sham-castrated and received either placebo or the plant extract. JPE reduced the ratio of widespread prostatic tumors in mice undergoing ADT, despite not affecting metastases. It also reduced the protein levels of the EMT drivers ZEB1 and N-Cadherin, apart from contributing to the maintenance of a periacinar layer primarily composed of smooth muscle cells. Mechanistically, JPE-induced effects in castrated mice involved decrease of AR protein expression as well as ERβ beneficial actions, which included a putative stimulation of TGF-β tumor-suppressive actions. In conclusion, JPE prevented the progression of poorly differentiated tumors with CRPC traits in the TRAMP model by hampering EMT and modulating steroid hormone and TGF-β signaling.