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Dietary protein restriction inhibits tumor growth in human xenograft models.

Fontana L, Adelaiye RM, Rastelli AL, Miles KM, Ciamporcero E, Longo VD, Nguyen H, Vessella R, Pili R - Oncotarget (2013)

Bottom Line: Inhibition of tumor growth correlated, in the LuCaP23.1 model, with decreased serum PSA and IGF-1 levels, down-regulation of mTORC1 activity, decreased cell proliferation as indicated by Ki67 staining, and reduction in epigenetic markers of prostate cancer progression, including the histone methyltransferase EZH2 and the associated histone mark H3K27me3.In addition, we observed that modifications of dietary protein quality, independently of protein quantity, decreased tumor growth.Our findings suggest that a reduction in dietary protein intake is highly effective in inhibiting tumor growth in human xenograft prostate and breast cancer models, possibly through the inhibition of the IGF/AKT/mTOR pathway and epigenetic modifications.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Washington University in St. Louis, MO, USA.

ABSTRACT

Purpose: Data from epidemiological and experimental studies suggest that dietary protein intake may play a role in inhibiting prostate and breast cancer by modulating the IGF/AKT/mTOR pathway. In this study we investigated the effects of diets with different protein content or quality on prostate and breast cancer.

Experimental design: To test our hypothesis we assessed the inhibitory effect of protein diet restriction on prostate and breast cancer growth, serum PSA and IGF-1 concentrations, mTOR activity and epigenetic markers, by using human xenograft cancer models.

Results: Our results showed a 70% inhibition of tumor growth in the castrate-resistant LuCaP23.1 prostate cancer model and a 56% inhibition in the WHIM16 breast cancer model fed with a 7% protein diet when compared to an isocaloric 21% protein diet. Inhibition of tumor growth correlated, in the LuCaP23.1 model, with decreased serum PSA and IGF-1 levels, down-regulation of mTORC1 activity, decreased cell proliferation as indicated by Ki67 staining, and reduction in epigenetic markers of prostate cancer progression, including the histone methyltransferase EZH2 and the associated histone mark H3K27me3. In addition, we observed that modifications of dietary protein quality, independently of protein quantity, decreased tumor growth. A diet containing 20% plant protein inhibited tumor weight by 37% as compared to a 20% animal dairy protein diet.

Conclusions: Our findings suggest that a reduction in dietary protein intake is highly effective in inhibiting tumor growth in human xenograft prostate and breast cancer models, possibly through the inhibition of the IGF/AKT/mTOR pathway and epigenetic modifications.

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Low protein diet decreases IGF-1 serum levels and inhibit LuCaP23.1-CR growth in combination with everolimus(A) Measurements of serum IGF-1 in LuCaP23.1-CR bearing animals fed with either 21% or 7% protein diet. (B, C) Mice were acclimatized for four weeks to either 21% or 7% protein diet and after LuCaP23.1-CR xenograft implantation were treated with everolimus (2 mg/kg PO, daily X5 times/week). (D, E) Endpoint PSA and tumor weights were collected. Results are expressed as the mean +/− SE, n=10.
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Figure 2: Low protein diet decreases IGF-1 serum levels and inhibit LuCaP23.1-CR growth in combination with everolimus(A) Measurements of serum IGF-1 in LuCaP23.1-CR bearing animals fed with either 21% or 7% protein diet. (B, C) Mice were acclimatized for four weeks to either 21% or 7% protein diet and after LuCaP23.1-CR xenograft implantation were treated with everolimus (2 mg/kg PO, daily X5 times/week). (D, E) Endpoint PSA and tumor weights were collected. Results are expressed as the mean +/− SE, n=10.

Mentions: To determine whether dietary protein intake affects circulating IGF-1 levels in castrated tumor bearing mice, serum IGF-1 concentration were measured in the two groups. Serum IGF-1 concentration was significantly lower in the 7% than in the 21% protein diet group (Fig. 2A). As both serum IGF-1 and amino acids levels are important regulators of mTORC1 activity, we were interested in determining whether or not a reduction in protein intake down-regulates the mTOR signaling pathway in the LuCaP23.1-CR model, and whether or not the diet-induced inhibitory effect on tumor growth was dependent on mTOR inhibition. To test this hypothesis, we assessed the effects on tumor growth and the levels of phosphorylated mTOR and p70 S6K in mice treated with diet alone versus diet in combination with everolimus treatment. As shown in figure 2B and C, everolimus treatment was as effective as protein restriction in inhibiting tumor growth and had greater effect in combination with protein restriction as compared to lower protein diet alone. Tumor weights from the animals treated with everolimus alone or the 7% protein diet alone were similar (Fig. 2D). However, tumor weights were significantly smaller in animals treated with everolimus fed the 7% protein diet than in those treated with everolimus fed the 20% protein diet, suggesting that protein restriction and mTOR inhibition have additive inhibitory effects on PCa development. Endpoint PSA measurements confirmed the inhibitory effect of protein restriction alone and everolimus in both the 21% and 7% protein diet groups (Fig. 2E). Immunohistochemistry staining showed a significant decrease in phospho-mTORC1 levels following protein restriction (21% protein diet =37% +/− 2.09 vs. 7% protein diet=19% +/− 2.03, p<0.0001, 95% CI = 14.51- 26.19), which was even more pronounced when protein restriction was combined with everolimus (Fig. 3A and B). We also observed a similar significant decrease in ribosomal protein TOR activity as indicated by the down-regulation of p70 S6K (21% protein diet =29%+/− 2.74 vs. 7% protein diet = 8%+/− 0.84, p<0.0001, 95% CI= 15.4-27.34) in mice fed the 7% protein diet, which is potentiated by everolimus treatment. Interestingly, associated with the reduced mTOR activity we observed a decreased number of proliferating cells as indicated by the Ki67 staining (21% protein diet = 47% +/− 4.5 vs. 7% protein diet = 22% +/− 3.4, p<0.0041, 95% CI= 11.55- 39.10) (Fig. 3A and B). Protein diet restriction induced a similar inhibition of mTOR pathway and Ki67 expression in another patient-derived xenograft model of PCa (supplementary Fig. S1).


Dietary protein restriction inhibits tumor growth in human xenograft models.

Fontana L, Adelaiye RM, Rastelli AL, Miles KM, Ciamporcero E, Longo VD, Nguyen H, Vessella R, Pili R - Oncotarget (2013)

Low protein diet decreases IGF-1 serum levels and inhibit LuCaP23.1-CR growth in combination with everolimus(A) Measurements of serum IGF-1 in LuCaP23.1-CR bearing animals fed with either 21% or 7% protein diet. (B, C) Mice were acclimatized for four weeks to either 21% or 7% protein diet and after LuCaP23.1-CR xenograft implantation were treated with everolimus (2 mg/kg PO, daily X5 times/week). (D, E) Endpoint PSA and tumor weights were collected. Results are expressed as the mean +/− SE, n=10.
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Figure 2: Low protein diet decreases IGF-1 serum levels and inhibit LuCaP23.1-CR growth in combination with everolimus(A) Measurements of serum IGF-1 in LuCaP23.1-CR bearing animals fed with either 21% or 7% protein diet. (B, C) Mice were acclimatized for four weeks to either 21% or 7% protein diet and after LuCaP23.1-CR xenograft implantation were treated with everolimus (2 mg/kg PO, daily X5 times/week). (D, E) Endpoint PSA and tumor weights were collected. Results are expressed as the mean +/− SE, n=10.
Mentions: To determine whether dietary protein intake affects circulating IGF-1 levels in castrated tumor bearing mice, serum IGF-1 concentration were measured in the two groups. Serum IGF-1 concentration was significantly lower in the 7% than in the 21% protein diet group (Fig. 2A). As both serum IGF-1 and amino acids levels are important regulators of mTORC1 activity, we were interested in determining whether or not a reduction in protein intake down-regulates the mTOR signaling pathway in the LuCaP23.1-CR model, and whether or not the diet-induced inhibitory effect on tumor growth was dependent on mTOR inhibition. To test this hypothesis, we assessed the effects on tumor growth and the levels of phosphorylated mTOR and p70 S6K in mice treated with diet alone versus diet in combination with everolimus treatment. As shown in figure 2B and C, everolimus treatment was as effective as protein restriction in inhibiting tumor growth and had greater effect in combination with protein restriction as compared to lower protein diet alone. Tumor weights from the animals treated with everolimus alone or the 7% protein diet alone were similar (Fig. 2D). However, tumor weights were significantly smaller in animals treated with everolimus fed the 7% protein diet than in those treated with everolimus fed the 20% protein diet, suggesting that protein restriction and mTOR inhibition have additive inhibitory effects on PCa development. Endpoint PSA measurements confirmed the inhibitory effect of protein restriction alone and everolimus in both the 21% and 7% protein diet groups (Fig. 2E). Immunohistochemistry staining showed a significant decrease in phospho-mTORC1 levels following protein restriction (21% protein diet =37% +/− 2.09 vs. 7% protein diet=19% +/− 2.03, p<0.0001, 95% CI = 14.51- 26.19), which was even more pronounced when protein restriction was combined with everolimus (Fig. 3A and B). We also observed a similar significant decrease in ribosomal protein TOR activity as indicated by the down-regulation of p70 S6K (21% protein diet =29%+/− 2.74 vs. 7% protein diet = 8%+/− 0.84, p<0.0001, 95% CI= 15.4-27.34) in mice fed the 7% protein diet, which is potentiated by everolimus treatment. Interestingly, associated with the reduced mTOR activity we observed a decreased number of proliferating cells as indicated by the Ki67 staining (21% protein diet = 47% +/− 4.5 vs. 7% protein diet = 22% +/− 3.4, p<0.0041, 95% CI= 11.55- 39.10) (Fig. 3A and B). Protein diet restriction induced a similar inhibition of mTOR pathway and Ki67 expression in another patient-derived xenograft model of PCa (supplementary Fig. S1).

Bottom Line: Inhibition of tumor growth correlated, in the LuCaP23.1 model, with decreased serum PSA and IGF-1 levels, down-regulation of mTORC1 activity, decreased cell proliferation as indicated by Ki67 staining, and reduction in epigenetic markers of prostate cancer progression, including the histone methyltransferase EZH2 and the associated histone mark H3K27me3.In addition, we observed that modifications of dietary protein quality, independently of protein quantity, decreased tumor growth.Our findings suggest that a reduction in dietary protein intake is highly effective in inhibiting tumor growth in human xenograft prostate and breast cancer models, possibly through the inhibition of the IGF/AKT/mTOR pathway and epigenetic modifications.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Washington University in St. Louis, MO, USA.

ABSTRACT

Purpose: Data from epidemiological and experimental studies suggest that dietary protein intake may play a role in inhibiting prostate and breast cancer by modulating the IGF/AKT/mTOR pathway. In this study we investigated the effects of diets with different protein content or quality on prostate and breast cancer.

Experimental design: To test our hypothesis we assessed the inhibitory effect of protein diet restriction on prostate and breast cancer growth, serum PSA and IGF-1 concentrations, mTOR activity and epigenetic markers, by using human xenograft cancer models.

Results: Our results showed a 70% inhibition of tumor growth in the castrate-resistant LuCaP23.1 prostate cancer model and a 56% inhibition in the WHIM16 breast cancer model fed with a 7% protein diet when compared to an isocaloric 21% protein diet. Inhibition of tumor growth correlated, in the LuCaP23.1 model, with decreased serum PSA and IGF-1 levels, down-regulation of mTORC1 activity, decreased cell proliferation as indicated by Ki67 staining, and reduction in epigenetic markers of prostate cancer progression, including the histone methyltransferase EZH2 and the associated histone mark H3K27me3. In addition, we observed that modifications of dietary protein quality, independently of protein quantity, decreased tumor growth. A diet containing 20% plant protein inhibited tumor weight by 37% as compared to a 20% animal dairy protein diet.

Conclusions: Our findings suggest that a reduction in dietary protein intake is highly effective in inhibiting tumor growth in human xenograft prostate and breast cancer models, possibly through the inhibition of the IGF/AKT/mTOR pathway and epigenetic modifications.

Show MeSH
Related in: MedlinePlus