Abstract
Phosphoinositide 3-kinase (PI3K) plays a critical role in tumorigenesis, and the PI3K p85 regulatory subunit exerts both positive and negative effects on signaling. Expression of Pik3r1, the gene encoding p85, is decreased in human prostate, lung, ovarian, bladder, and liver cancers, consistent with the possibility that p85 has tumor suppressor properties. We tested this hypothesis by studying mice with a liver-specific deletion of the Pik3r1 gene. These mice exhibited enhanced insulin and growth factor signaling and progressive changes in hepatic pathology, leading to the development of aggressive hepatocellular carcinomas with pulmonary metastases. Liver tumors that arose exhibited markedly elevated levels of phosphatidylinositol (3,4,5)-trisphosphate, along with Akt activation and decreased PTEN expression, at both the mRNA and protein levels. Together, these results substantiate the concept that the p85 subunit of PI3K has a tumor-suppressive role in the liver and possibly other tissues.
Highlights
The class IA phosphoinositide 3-kinase (PI3K) pathway plays a central role in growth factor signaling and oncogenesis
Over the past 2 decades, a number of studies have shown an integral role of PI3K in tumorigenesis
This can occur through direct activation of PI3K by oncoproteins, such as polyoma middle T and receptor tyrosine kinase (RTK), deletion of the PIP3 phosphatase PTEN, and genetic mutation of proteins in the PI3K signaling pathway, including p85, 5312 Cancer Res; 70(13) July 1, 2010
Summary
The class IA phosphoinositide 3-kinase (PI3K) pathway plays a central role in growth factor signaling and oncogenesis. On activation of a receptor tyrosine kinase (RTK), PI3K is activated and generates the second messenger phosphatidylinositol [3,4,5]-trisphosphate (PIP3), which activates critical downstream targets such as Akt and mammalian target of rapamycin (mTOR). The PI3K pathway has a causal role in many forms of cancer, including those of the breast [1], colon [2], and liver [3]. Authors' Affiliations: 1Joslin Diabetes Center and Departments of 2Pathology and 3Systems Biology, Harvard Medical School; 4Center for Molecular Imaging Research, Department of Radiology, Massachusetts General Hospital; 5Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts; 6Department of Metabolic Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; and 7Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts.
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