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Oncogenic signaling of class I PI3K isoforms

A Denley1, S Kang, U Karst

  • 1Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.

Oncogene
|November 14, 2007
PubMed

Insights

Overexpression of non-alpha PI3K isoforms (p110beta, p110gamma, p110delta) drives cancer cell transformation. These isoforms signal through Akt/mTOR, impacting key cellular pathways and offering potential therapeutic targets.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Class I phosphoinositide 3-kinases (PI3Ks) have four catalytic isoforms: p110α, p110β, p110δ, and p110γ.
  • While cancer-specific mutations are known for p110α, the oncogenic mechanisms of other isoforms remain unclear.
  • Overexpression of wild-type p110β, p110γ, or p110δ can induce cellular transformation.

Purpose of the Study:

  • To elucidate the signaling mechanisms by which non-alpha isoforms of class I PI3K mediate oncogenic signals.
  • To investigate the role of specific pathways, such as Erk, and protein interactions, like Ras, in isoform-specific transformation.
  • To evaluate the efficacy of small molecule inhibitors against oncogenic PI3K signaling.

Main Methods:

  • Investigated signaling pathways including Akt/mTOR, GSK3β, and FoxO1 degradation.
  • Assessed the requirement of the Erk pathway for transformation induced by different PI3K isoforms.
  • Examined the impact of Ras interaction and C2 domain mutations on transformation and membrane association.
  • Utilized small molecule inhibitors targeting class I PI3K isoforms and MEK inhibitors.

Main Results:

  • Potently transforming class I PI3K isoforms signal via Akt/mTOR, inhibit GSK3β, and degrade FoxO1.
  • Erk pathway is essential for p110γ and p110β transformation, but not for p110δ or p110α (H1047R mutant).
  • Transformation by p110γ and p110β depends on Ras interaction, while p110δ transformation is affected by C2 domain mutations impacting membrane association.
  • Specific small molecule inhibitors effectively block oncogenic signaling and transformation for all class I PI3K isoforms.

Conclusions:

  • Non-alpha PI3K isoforms (p110β, p110γ, p110δ) mediate oncogenic signals through Akt/mTOR, GSK3β inhibition, and FoxO1 degradation.
  • Isoform-specific dependencies on Erk and Ras highlight distinct mechanisms of transformation.
  • Small molecule inhibitors targeting PI3K isoforms, especially in combination with MEK inhibitors, show promise for cancer therapy.

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