Effects of omega-3 fatty acids on the modulation of prostate carcinogenesis in TRAMP mice

Author(s)

Alana Della Torre da Silva

• Document type: Master's Dissertation
• Press: São José do Rio Preto. 2021-09-24.
• Institution: Universidade Estadual Paulista (Unesp). Instituto de Biociências Letras e Ciências Exatas. São José do Rio Preto
• Defense date: 2021-09-02
• Advisor: Rejane Maira Góes

Abstract

Prostate adenocarcinoma (CaP) is the most common cancer in men worldwide and the second leading cause of death by cancer-related cases in Brazil. The intake of omega-3 polyunsaturated fatty acids (ω3), such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), has been linked to lower risk of CaP development and positive prognostic, however, data regarding ω3 intake is still conflicting and inconclusive. Here, we evaluated the effects of a DHA/EPA-enriched diet (Dω3) in tumor progression in the dorsolateral lobe (LDL) of the prostate of the transgenic adenocarcinoma of the mouse prostate (TRAMP mice), and the impact on regulated cell death using both in vivo and in vitro approaches. Mice (8 wk) were fed for 1 or 3 months with a diet containing 10% fish oil (groups T12 and T20, respectively) or a standard rodent diet (groups C12 and C20). Additionally, 8 wk-old-mice fed standard diet (C8) were also analyzed once the proliferative disorders began to develop at this age. LDLs were processed for histopathological, stereological, immunohistochemical, TUNEL, and activated caspase 3 assays. Dω3 for 1 month increased the frequency of healthy epithelial areas (2.4x) and reduced the frequency of both premalignant lesions (2.7x) and carcinoma in situ (2.3x) compared to the control groups. Half of the animals at 20 weeks of age developed primary tumors regardless of their diet and there was no variation in tumor weight between these groups. However, T20 animals that did not develop primary tumors for which LDL was properly isolated displayed and an increase in the frequency of healthy epithelial areas (2.2x) and a reduction of premalignant lesions (2.9x) and carcinoma in situ (2.9x) in this lobe compared to C20. The morphology of LDL in T12 and T20 groups and the frequencies of acinar epithelium, lumen, and stromal areas remained similar to those of C8. In both periods, Dω3 reduced cell proliferation and tissue expression of AR and ER-α in the epithelium. It also maintained the stromal characteristics, preventing the increase in collagen fibers, α-SMA+ cells, and T-CD3+ lymphocytes that occurs during disease progression. Dω3 increased autophagy in both groups, but only the T20 group display an increase in apoptosis rate (31.25%), and no differences were observed in necroptosis and pyroptosis, which were more frequent restricted to stromal immune cells. Treatment of the benign prostatic epithelial (PNT1A) and androgen-responsive (22rv1) cell lines with DHA (100µM, 48h), showed that this ω3 increases autophagy by 8.6% and inhibits 27.3% pyroptosis in the tumor lineage, whereas it reduces necroptosis (50%) in the benign cell line. Thus, our data indicate that dietary intervention with ω3 in the shortest period decreases the severity of the disease and delays tumor progression in TRAMP mice, via downregulation of tissue expression of AR and ER-α, decrease of proliferative activity, modulation of regulated cell death and improvement of the stromal microenvironment. These findings suggest a protective action of ω3 on CaP and highlight its possible application as a therapeutic adjuvant in the early stages of the disease although it reinforces the need for further studies of its impact in advanced stages of the disease. (AU)

• FAPESP's process: 19/15109-4 - Effects of docosahexaenoic acid on the modulation of cell cycle and cell death at prostatic carcinogenesis
• Grantee: Alana Della Torre da Silva
• Support Opportunities: Scholarships in Brazil - Master