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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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PIK3CA activating mutations or PTEN loss suppress tumour sensitivity to DRa, 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.
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Figure 3: PIK3CA activating mutations or PTEN loss suppress tumour sensitivity to DRa, 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.

Mentions: The correlation between tumour sensitivity to DR and the activation status of the PI3K pathway led us to hypothesize that constitutive PI3K signaling in tumour cells is sufficient to decrease the sensitivity of tumours to DR. To begin testing this idea, we used two cell lines derived from the DLD-1 colorectal cancer cell line21. These cells are isogenic except that one carries a wild-type (DLD-WT) and the other (DLD-Mut) a constitutively active mutant allele (E545K) of PIK3CA. Consistent with their genetic statuses, DLD-Mut but not DLD-WT cells maintained high levels of phospho-S473 Akt upon serum withdrawal for 1 or 24 hours (Fig. 3a). The growth responses of the DLD-Mut and DLD-WT cells in culture to increasing concentrations of insulin or IGF-1 (Fig. 3b, c) were reminiscent of those of the cancer lines that form DR-resistant and DR-sensitive tumours, respectively (Fig. 2).


Tumours with PI3K activation are resistant to dietary restriction.

Kalaany NY, Sabatini DM - Nature (2009)

PIK3CA activating mutations or PTEN loss suppress tumour sensitivity to DRa, 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.
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Figure 3: PIK3CA activating mutations or PTEN loss suppress tumour sensitivity to DRa, 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.
Mentions: The correlation between tumour sensitivity to DR and the activation status of the PI3K pathway led us to hypothesize that constitutive PI3K signaling in tumour cells is sufficient to decrease the sensitivity of tumours to DR. To begin testing this idea, we used two cell lines derived from the DLD-1 colorectal cancer cell line21. These cells are isogenic except that one carries a wild-type (DLD-WT) and the other (DLD-Mut) a constitutively active mutant allele (E545K) of PIK3CA. Consistent with their genetic statuses, DLD-Mut but not DLD-WT cells maintained high levels of phospho-S473 Akt upon serum withdrawal for 1 or 24 hours (Fig. 3a). The growth responses of the DLD-Mut and DLD-WT cells in culture to increasing concentrations of insulin or IGF-1 (Fig. 3b, c) were reminiscent of those of the cancer lines that form DR-resistant and DR-sensitive tumours, respectively (Fig. 2).

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