Evaluation of mitochondrial bioenergetics and oxidative stress in human prostate cells treated with docosahexaenoic acid and melatonin

Author(s)

Guilherme Henrique Tamarindo

• Document type: Master's Dissertation
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia
• Defense date: 2017-06-02

Examining board members

Rejane Maira Góes; Ana Angélica Henrique Fernandes; Wagner José Fávaro

• Advisor: Fernanda Ramos Gadelha; Marina Guimarães Gobbo; Rejane Maira Góes

Abstract

Prostate Cancer (PCa) is among the five main causes of death in world scenario and early diagnosis limitations may contribute to this higher mortality index. In this line, strategies have been investigated with focus on prevention and decrease of risks to develop PCa. Docosahexaenoic acid (DHA) and melatonin (MLT) have been suggested as antitumor agents and there are strong evidences of mitochondria role in their effects, but is not completely elucidated. In this context, our aim was to evaluate chemoprevention potential of DHA in decrease survivor and proliferation of PNT1A cells mediated by increase of oxidative stress, as well as if MLT exert same effect by modulating mitochondria bioenergetics. Moreover, we tested if combined they exhibited amplified effect. Firstly, we conclude that: (1) DHA exerted hormetic behavior by stimulating at lower concentrations cell proliferation and decreasing at highest molarity 100µM when exposed for 48h and 72h; (2) MLT displayed anticlonogenic effect from 1µM which was amplified when co-incubated with lipid. Antiproliferative effect of DHA (100µM) and MLT (1µM) at 48h indicated that: (3) omega-3 increased oxidative stress followed by area and mitochondrial perimeter, parameters reduced by MLT; (5) indole alone or in combination with fatty acid ameliorated oxidative phosphorylation and recovered cell capacity to respond to stress situation provoked by DHA; (5) MLT increased and DHA reduced intracellular glycogen accumulation; (6) isolated or combined, treatments inactivated AKT, MLT alone suppressed mTOR and when co-incubated activated ERK1/2 pathway; (7) hormone co-incubated with DHA increased GSTP1 expression; (8) treatments did not change AR expression, but MLT stimulated testosterone uptake by PNT1A cells; and (9) indole effects observed in our study were not dependent of MTR1 and MTR2 receptors sensitization. On the other hand, DHA increased cell proliferation (50µM-48h, the highest rate achieved), probably due to citoplasmatic retention of PPAR?. In conclusion, our results suggest wariness with DHA supplementation with regard to lipid role in encourage or inhibit cell proliferation. Besides that, both chemopreventive property, isolated or in combination, was revealed and point to oxidative stress, mainly mitochondria, as relevant targets in decrease of survivor of prostatic epithelial cells with pre-malignant alterations (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