Background: Environmental factors such as a Western diet may be associated with the risk of developing prostate cancer (PCa). Diet modifications such as calorie and fat restriction have been shown to have an impact on PCa development and progression. Protein diet restriction has been associated with epigenetic changes in embrional development. The aim of this study was to assess the effect of protein restriction on prostate tumor progression. Methods: A human xenograft LuCaP 23.1 castrate resistant (AI) model, which resembles the pathological features of human prostate cancer including prostate specific antigen (PSA) expression, was utilized. SCID mice were randomly grouped and placed on either regular (21%) or low (7%) protein isocaloric diet. LuCaP 23.1 AI tumor tissue was implanted 4 weeks either before or after diet modifications. To investigate whether the source of protein diet had an impact on tumor growth, we randomly grouped mice and placed them prior to tumor implantation on either normal plant protein diet (20%), low plant based protein diet (10%), normal dairy protein diet (20%) or low diary protein diet (10%). We assessed tumor growth two times a week and body weight once a week. Endpoint tumor weights were assessed and tumor samples were collected for immunohistochemistry (IHC) studies. Body fluids were collected for IGF-1 and glucose level analysis. Results: Our preliminary results showed a >70% inhibition of tumor growth in LuCaP23.1 AI model with 7% low protein diet when compared to 21% normal protein diet (p >0.01). Tumor inhibition correlated with a decrease in PSA values. Tumor growth assessment also indicated that 20% and 10% plant protein, and 10% dairy protein diet decreased tumor weight by 37% (20% and 10% plant protein) and 35% (10% dairy protein) as compared to 20% animal protein diet (p >0.05). Serum glucose levels were higher in mice on low protein diet (150.3mg/dL+22.4) as compared to those on normal diet (136.6mg/dL+17.6). IHC analysis showed a decrease in proliferation as suggested by Ki67 staining (21% diet = 47%+4.4 vs. 7% diet = 22%+3.4), inhibition of mTORC1 activity as demonstrated by a reduction in phosphor-mTOR (21% diet = 54%+2.7 vs. 7% diet = 21%+2.7) and its downstream enzyme phosphor-S6 (21% diet = 52%+4.0 vs. 7% diet = 5.4%+0.5). In addition, low protein diet decreased the level of the histone methyltransferase EZH2 (21% diet = 97.3% +1.69 vs. 7% diet = 55.1%+3.46) and the associated repressive histone mark H3K27me3 (21% diet = 82.3%+5.1 vs. 7% diet = 54.9%+3.8). Additional animal models for PCa are being tested. Conclusions: Our findings suggest that a reduction in animal protein diet is effective in inhibiting tumor growth in a human xenograft PCa model. Tumor inhibition following protein restriction was associated with modifications of mTOR signaling pathway and epigenetic marks. These data provide a rationale for protein diet modifications in patients with PCa.
Citation Format: Remi M. Adelaiye, Kiersten Marie Miles, Eric Ciamporcero, Holly Nguyen, Robert Vessella, Luigi Fontana, Roberto Pili. Tumor growth inhibition and epigenetic changes following protein diet restriction in a human prostate cancer model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4859. doi:10.1158/1538-7445.AM2013-4859