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Tumours with PI3K activation are resistant to dietary restriction.

Kalaany NY, Sabatini DM - Nature (2009)

Bottom Line: 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.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.Dietary restriction does not affect a PTEN- mouse model of prostate cancer, but it significantly decreases tumour burden in a mouse model of lung cancer lacking constitutive PI3K signalling.

View Article: PubMed Central - PubMed

Affiliation: Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA.

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- 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- 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.

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Constitutive PI3K activation correlates with tumour resistance to DRa,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.
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Figure 2: Constitutive PI3K activation correlates with tumour resistance to DRa,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.

Mentions: Because the xenografted tumours responded differentially to DR despite similar decreases in insulin and IGF-1 levels, we determined whether the six cancer cell lines studied have differential requirements for these factors for their growth in tissue culture. Indeed, in cell lines that form DR-sensitive tumours (MDA-MB-231, MDA-MB-435, and SW620) insulin or IGF-1 caused a dose-dependent increase in cell numbers (Fig. 2a). In contrast, cell lines that generate DR-resistant tumours (MCF10DCIS, U87-MG, PC3) grew in culture in an insulin and IGF-1-independent fashion (Fig. 2b).


Tumours with PI3K activation are resistant to dietary restriction.

Kalaany NY, Sabatini DM - Nature (2009)

Constitutive PI3K activation correlates with tumour resistance to DRa,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.
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Related In: Results  -  Collection

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Figure 2: Constitutive PI3K activation correlates with tumour resistance to DRa,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.
Mentions: Because the xenografted tumours responded differentially to DR despite similar decreases in insulin and IGF-1 levels, we determined whether the six cancer cell lines studied have differential requirements for these factors for their growth in tissue culture. Indeed, in cell lines that form DR-sensitive tumours (MDA-MB-231, MDA-MB-435, and SW620) insulin or IGF-1 caused a dose-dependent increase in cell numbers (Fig. 2a). In contrast, cell lines that generate DR-resistant tumours (MCF10DCIS, U87-MG, PC3) grew in culture in an insulin and IGF-1-independent fashion (Fig. 2b).

Bottom Line: 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.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.Dietary restriction does not affect a PTEN- mouse model of prostate cancer, but it significantly decreases tumour burden in a mouse model of lung cancer lacking constitutive PI3K signalling.

View Article: PubMed Central - PubMed

Affiliation: Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA.

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- 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- 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.

Show MeSH
Related in: MedlinePlus