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Tumours with PI3K activation are resistant to dietary restriction

Nada Y Kalaany1, David M Sabatini

  • 1Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA.

Nature
|March 13, 2009
PubMed

Insights

Dietary restriction impacts tumor growth, but resistance is linked to the phosphatidylinositol-3-kinase (PI3K) pathway. Activating mutations in PI3K make tumors resistant to dietary restriction, suggesting targeted therapies.

Area of Science:

  • Oncology
  • Metabolic pathways
  • Cancer biology

Background:

  • Dietary restriction (DR) is known to delay tumor incidence and slow tumor growth.
  • The underlying mechanisms for tumor sensitivity or resistance to DR are not fully understood.

Purpose of the Study:

  • To investigate the molecular mechanisms determining cancer cell sensitivity to dietary restriction.
  • To identify specific pathways that confer resistance to the anti-growth effects of DR.

Main Methods:

  • Utilized human cancer cell lines grown as tumor xenografts in mice.
  • Compared tumor growth and sensitivity to DR in cell lines with varying PI3K pathway activation.
  • Genetically modified cancer cells to alter PI3K pathway activity (e.g., substituting mutant PI3K with wild-type, restoring PTEN expression).
  • Evaluated DR effects in PTEN-null mouse models of prostate cancer and a lung cancer model lacking constitutive PI3K signaling.

Main Results:

  • Cancer cell lines with constitutively activated phosphatidylinositol-3-kinase (PI3K) pathway exhibited resistance to DR's anti-growth effects.
  • These resistant cells could proliferate independently of insulin or insulin-like growth factor 1.
  • Restoring wild-type PI3K or PTEN expression converted resistant tumors to a DR-sensitive phenotype.
  • DR did not impact PTEN-null prostate cancer growth but reduced tumor burden in a PI3K-independent lung cancer model.

Conclusions:

  • The PI3K pathway is a critical determinant of tumor sensitivity to dietary restriction.
  • Activating mutations in the PI3K pathway confer resistance to DR.
  • These findings suggest that PI3K pathway activation status may predict cancer response to DR-mimetic therapies.

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