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Oncogenic signaling of class I PI3K isoforms
1Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Oncogene
|November 14, 2007
Summary
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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