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, 458 (7239), 725-31

Tumours With PI3K Activation Are Resistant to Dietary Restriction

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Tumours With PI3K Activation Are Resistant to Dietary Restriction

Nada Y Kalaany et al. Nature.

Abstract

Dietary restriction delays the incidence and decreases the growth of various types of tumours, but the mechanisms underlying the sensitivity of tumours to food restriction remain unknown. Here we show that certain human cancer cell lines, when grown as tumour xenografts in mice, are highly sensitive to the anti-growth effects of dietary restriction, whereas others are resistant. Cancer cells that form dietary-restriction-resistant tumours carry mutations that cause constitutive activation of the phosphatidylinositol-3-kinase (PI3K) pathway and in culture proliferate in the absence of insulin or insulin-like growth factor 1. Substitution of an activated mutant allele of PI3K with wild-type PI3K in otherwise isogenic cancer cells, or the restoration of PTEN expression in a PTEN-null cancer cell line, is sufficient to convert a dietary-restriction-resistant tumour into one that is dietary-restriction-sensitive. Dietary restriction does not affect a PTEN-null mouse model of prostate cancer, but it significantly decreases tumour burden in a mouse model of lung cancer lacking constitutive PI3K signalling. Thus, the PI3K pathway is an important determinant of the sensitivity of tumours to dietary restriction, and activating mutations in the pathway may influence the response of cancers to dietary restriction-mimetic therapies.

Figures

Figure 1
Figure 1. Human tumour xenografts display differential sensitivities to dietary restriction
a,b, Volumes of six different subcutaneous (a) or two orthotopic human tumour xenografts (b) in NOD/SCID mice that were either ad-libitum fed (AL) or dietary restricted (DR). N= 6 to 12 tumours. Data are means ± s.e.m. * indicates P < 0.05.
Figure 2
Figure 2. Constitutive PI3K activation correlates with tumour resistance to DR
a,b, Proliferation curves of cancer cells that form DR-sensitive (a) and DR-resistant (b) tumours cultured in the presence of increasing concentrations of insulin or IGF-1. Data points represent means ± s.e.m for n = 6. * indicates P ≤ 0.001 for differences between 0 ng/ml and 1000 ng/ml insulin or 0 ng/ml and 100 ng/ml IGF-1 at day 5. c, Phospho-S473 Akt and total Akt levels in cells grown in the presence or absence of serum for 1 or 24 hours. d, PTEN expression, phospho-S473 Akt and total Akt levels in the different cell lines. e, Sequencing results for PIK3CA hot-spot mutations, loss of or mutational status of PTEN, TP53, RAS and BRAF in all cell lines studied. WT refers to wild-type; mut to mutant, and nd to not determined. “–“ indicates absence of the gene.
Figure 3
Figure 3. PIK3CA activating mutations or PTEN loss suppress tumour sensitivity to DR
a, Phospho-S473 Akt and total Akt levels in DLD-WT and DLD-Mut cells in the presence or absence of serum for 1 or 24 hours. b, c, and f, Proliferation curves of DLD-WT, DLD-Mut, and doxycycline(Dox)-treated (1µg/ml) U87-MG cells in the presence of increasing concentrations of insulin or IGF-1, n=6. * indicates P ≤ 0.001 as in Fig. 2a, b. d, Volumes of DLD-WT and DLD-Mut tumours in AL or DR mice (n= 7–10). e, PTEN, phospho-S473 Akt and total Akt levels in U87-MG cells in the presence or absence of Dox (left panel) and in Dox-treated U87-MG cells in the presence or absence of serum for 1 hour or 24 hours (right panel). g, Volumes of U87-MG tumours in AL and DR mice administered drinking water with or without Dox (n= 7–9). Data in b, c, d, f and g represent means ± s.e.m.
Figure 4
Figure 4. Effects of modulation of PI3K signaling on the apoptotic response of tumours to DR
a-d, Immunohistochemical analyses of FOXO1 (a, b) and cleaved caspase-3 (c, d) in tumours formed by DLD-WT and DLD-Mut cells and by the PTEN-inducible U87-MG cells in mice treated or non-treated with doxycycline (Dox). Graphs to right of images indicate percent of total cells that are positive for cleaved caspase-3. Data in c and d graphs are means ± s.e.m, measured in 9 images (1000 nuclei counted per image) from 3 different tumours per group. ** indicates P ≤ 0.01. All images were acquired at the same magnification and scale bar = 20 µm. Framed inserts in a and b are a 3.9-fold magnification of a representative area of the corresponding larger image. Arrows point to immunoreactivity for FOXO1 (a, b) or cleaved caspase-3 (c and d).
Figure 5
Figure 5. A K-RAS mouse model of lung cancer but not a PTEN-null model of prostate cancer is sensitive to DR
a, Representative images of lungs and average diameter of tumour nodules on the surface of the lungs (graph) of 7-week-old K-RASLA2; P53 LSL/ WT mice under AL or DR conditions (n=3). b-d, H&E staining (b) and immunohistochemical analyses of Ki-67 (c) and cleaved caspase-3 (d) in sections prepared from lungs in a. e-h, H&E staining (e) and immunohistochemical analyses of phospho-Akt S473 (f), Ki-67 (g), and cleaved caspase-3 (h) in prostates of 11-week-old Probasin-Cre; PTEN L/L mice under AL or DR conditions. In c, d, g, and h, graphs to right of respective images indicate percent of total cells that are positive for Ki-67 or cleaved caspase-3. Graphs show means ± s.e.m. of percent of proliferating (c and g) or apoptotic cells (d and h) measured in 10 images (1000 nuclei counted per image) from 2 different tumours per group. All pictures were captured under the same magnification and scale bar = 20 µm. ** indicates P = 8.3 × 10−8.

Comment in

  • Cancer: When Restriction Is Good
    A Brunet. Nature 458 (7239), 713-4. PMID 19360073.
    Dietary restriction can prolong life and delay the onset of cancer. Suppressing the signalling pathway that is mediated by the hormone insulin might be crucial for the an …

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References

    1. Moreschi C. Beziehung zwischen Ernahrung und Tumorwachstum. Z. Immunitatsforsch. 1909;2:651–675.
    1. Rous P. The influence of diet on transplanted and spontaneous tumors. Exp. Med. 1914;20:351–413. - PMC - PubMed
    1. McCay CM, Crowell MF, Maynard LA. The effect of retarded growth upon the length of life span and upon the ultimate body size. J. Nutr. 1935;18:63–79. - PubMed
    1. Tannenbaum A, Silverstone H. The influence of the degree of caloric restriction on the formation of skin tumors and hepatomas in mice. Cancer Res. 1949;9:724–727. - PubMed
    1. Tannenbaum A, Silverstone H. Effect of limited food intake on survival of mice bearing spontaneous mammary carcinoma and on the incidence of lung metastases. Cancer Res. 1953;13:532–536. - PubMed

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