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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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Related in: MedlinePlus

Low protein diet attenuates the growth of prostate and breast cancer in the castrate-resistant LuCaP23.1 model and in the WHIM16 model, respectivelyTumor sizes were assessed two times a week by caliper measurements. (A, B) LuCaP23.1-CR and (G) WHIM16 growth curve of tumors already exposed to low protein diet (pre-implantation studies) and endpoint tumor weights. (E, F) LuCap23.1-CR growth curve of tumors exposed to low protein diet after tumors were implanted and established (post-implantation studies), and endpoint tumor weights. (C) LuCaP23.1-CR and (H) WHIM16 mouse body weights. (D) Measurements of serum glucose in LuCaP23.1-CR bearing mice. Results are expressed as the mean +/− SE, n= 7-10; * p<0.05.
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Figure 1: Low protein diet attenuates the growth of prostate and breast cancer in the castrate-resistant LuCaP23.1 model and in the WHIM16 model, respectivelyTumor sizes were assessed two times a week by caliper measurements. (A, B) LuCaP23.1-CR and (G) WHIM16 growth curve of tumors already exposed to low protein diet (pre-implantation studies) and endpoint tumor weights. (E, F) LuCap23.1-CR growth curve of tumors exposed to low protein diet after tumors were implanted and established (post-implantation studies), and endpoint tumor weights. (C) LuCaP23.1-CR and (H) WHIM16 mouse body weights. (D) Measurements of serum glucose in LuCaP23.1-CR bearing mice. Results are expressed as the mean +/− SE, n= 7-10; * p<0.05.

Mentions: To test the hypothesis whether a isocaloric decrease in dietary protein intake inhibits tumor growth in a human animal model of PCa and BC, we first designed and tested murine diets containing the lowest concentrations of protein that did not result in weight loss or health impairment. These studies showed that an “ad libitum” fed diet providing 7% calories from protein provided the lowest protein level compatible with health and weight maintenance (data not shown). In our first experiment (pre-implantation study), we acclimatized 4-6 week old male SCID mice to either the 21% or 7% protein diet for 4 weeks, prior to surgical castration and subcutaneous implantation of LuCaP23.1-CR tumors. As shown in figure 1A, LuCap23.1-CR xenograft growth was strikingly reduced in the 7% than in the 20% protein diet group, resulting in a 70% (p< 0.001, 95% CI= 55.98 to 139.7) reduced tumor size at 5 weeks post tumor implantation. Consistently, average tumor weight at the end of the experiment was 81% (p<0.0009, 95% CI =0.3814-1.243) lower in the 7% protein than in the 20% protein diet group (Fig. 1B). In a second experiment (post-implantation study), protein restriction was initiated in castrated mice 4 weeks after tumor establishment (~50 mm2). As shown in figure 1E, also in this setting the 7% protein diet markedly inhibited tumor growth and resulted in a ~50% (p<0.0275, 95% CI = 0.04232-0.5910) reduction in tumor weight (Fig.1F). Throughout the 4-month study, there was no significant difference in mean body weights between the 7% and the 21% protein diet groups (Fig. 1C). Interestingly, despite the higher carbohydrate content of the 7% protein diet, there was no significant difference in serum glucose concentration between the two groups (Fig. 1D).


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 attenuates the growth of prostate and breast cancer in the castrate-resistant LuCaP23.1 model and in the WHIM16 model, respectivelyTumor sizes were assessed two times a week by caliper measurements. (A, B) LuCaP23.1-CR and (G) WHIM16 growth curve of tumors already exposed to low protein diet (pre-implantation studies) and endpoint tumor weights. (E, F) LuCap23.1-CR growth curve of tumors exposed to low protein diet after tumors were implanted and established (post-implantation studies), and endpoint tumor weights. (C) LuCaP23.1-CR and (H) WHIM16 mouse body weights. (D) Measurements of serum glucose in LuCaP23.1-CR bearing mice. Results are expressed as the mean +/− SE, n= 7-10; * p<0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3926840&req=5

Figure 1: Low protein diet attenuates the growth of prostate and breast cancer in the castrate-resistant LuCaP23.1 model and in the WHIM16 model, respectivelyTumor sizes were assessed two times a week by caliper measurements. (A, B) LuCaP23.1-CR and (G) WHIM16 growth curve of tumors already exposed to low protein diet (pre-implantation studies) and endpoint tumor weights. (E, F) LuCap23.1-CR growth curve of tumors exposed to low protein diet after tumors were implanted and established (post-implantation studies), and endpoint tumor weights. (C) LuCaP23.1-CR and (H) WHIM16 mouse body weights. (D) Measurements of serum glucose in LuCaP23.1-CR bearing mice. Results are expressed as the mean +/− SE, n= 7-10; * p<0.05.
Mentions: To test the hypothesis whether a isocaloric decrease in dietary protein intake inhibits tumor growth in a human animal model of PCa and BC, we first designed and tested murine diets containing the lowest concentrations of protein that did not result in weight loss or health impairment. These studies showed that an “ad libitum” fed diet providing 7% calories from protein provided the lowest protein level compatible with health and weight maintenance (data not shown). In our first experiment (pre-implantation study), we acclimatized 4-6 week old male SCID mice to either the 21% or 7% protein diet for 4 weeks, prior to surgical castration and subcutaneous implantation of LuCaP23.1-CR tumors. As shown in figure 1A, LuCap23.1-CR xenograft growth was strikingly reduced in the 7% than in the 20% protein diet group, resulting in a 70% (p< 0.001, 95% CI= 55.98 to 139.7) reduced tumor size at 5 weeks post tumor implantation. Consistently, average tumor weight at the end of the experiment was 81% (p<0.0009, 95% CI =0.3814-1.243) lower in the 7% protein than in the 20% protein diet group (Fig. 1B). In a second experiment (post-implantation study), protein restriction was initiated in castrated mice 4 weeks after tumor establishment (~50 mm2). As shown in figure 1E, also in this setting the 7% protein diet markedly inhibited tumor growth and resulted in a ~50% (p<0.0275, 95% CI = 0.04232-0.5910) reduction in tumor weight (Fig.1F). Throughout the 4-month study, there was no significant difference in mean body weights between the 7% and the 21% protein diet groups (Fig. 1C). Interestingly, despite the higher carbohydrate content of the 7% protein diet, there was no significant difference in serum glucose concentration between the two groups (Fig. 1D).

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