Melatonin and Docosahexaenoic Acid Decrease Proliferation of PNT1A Prostate Benign Cells via Modulation of Mitochondrial Bioenergetics and ROS Production

Author(s)

Tamarindo, Guilherme H. ; Ribeiro, Daniele L. ; Gobbo, Marina G. ; Guerra, Luiz H. A. ; Rahal, Paula ; Taboga, Sebastiao R. ; Gadelha, Fernanda R. ; Goes, Rejane M.

• Document type: Journal article
• Source: OXIDATIVE MEDICINE AND CELLULAR LONGEVITY; v. 2019, p. 15-pg., 2019-01-01.

Abstract

Prostate cancer development has been associated with changes in mitochondria' activity and reactive oxygen species (ROS) production. Melatonin (MLT) and docosahexaenoic acid (DHA) have properties to modulate both, but their protective role, mainly at early stages of prostate cancer, remains unclear. In this study, the effects of MLT and DHA, combined or not, on PNT1A cells with regard to mitochondria bioenergetics, ROS production, and proliferation-related pathways were examined. Based on dose response and lipid accumulation assays, DHA at 100 mu M and MLT at 1 mu M for 48 h were chosen. DHA doubled and MLT reduced (40%) superoxide anion production, but coincubation (DM) did not normalize to control. Hydrogen peroxide production decreased after MLT incubation only (p < 0.01). These alterations affected the area and perimeter of mitochondria, since DHA increased whereas MLT decreased, but such hormone has no effect on coincubation. DHA isolated did not change the oxidative phosphorylation rate (OXPHOS), but decreased (p < 0.001) the mitochondria' bioenergetic reserve capacity (MBRC) which is closely related to cell responsiveness to stress conditions. MLT, regardless of DHA, ameliorated OXPHOS and recovered MBRC after coincubation. All incubations decreased AKT phosphorylation; however, only MLT alone inhibited p-mTOR. MLT increased p-ERK1/2 and, when combined to DHA, increased GSTP1 expression (p < 0.01). DHA did not change the testosterone levels in the medium, whereas MLT alone or coincubated decreased by about 20%; however, any incubation affected AR expression. Moreover, incubation with luzindole revealed that MLT effects were MTR1/2-independent. In conclusion, DHA increased ROS production and impaired mitochondrial function which was probably related to AKT inactivation; MLT improved OXPHOS and decreased ROS which was related to AKT/mTOR dephosphorylation, and when coincubated, the antiproliferative action was related to mitochondrial bioenergetic modulation associated to AKT and ERK1/2 regulation. Together, these findings point to the potential application of DHA and MLT towards the prevention of proliferative prostate diseases. (AU)

• FAPESP's process: 15/13371-2 - Evaluation of mitochondrial bioenergetics and oxidative stress in human prostate cells treated with docosahexaenoic acid and melatonin
• Grantee: Guilherme Henrique Tamarindo
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 13/16368-7 - Influence of exogen melatonin on rat prostate tissue response to experimental diabetes and interference on androgen and insulin actions
• Grantee: Rejane Maira Góes
• Support Opportunities: Regular Research Grants
• FAPESP's process: 15/24595-9 - Correlation between the biochemical parameters of Trypanosoma cruzi isolates from Chagas disease patients with different clinical forms of the disease and the pathogenesis of the disease
• Grantee: Fernanda Ramos Gadelha
• Support Opportunities: Regular Research Grants