Essential role of Stat3 in PI3K-induced oncogenic transformation.

Abstract

Cells transformed by the p110α-H1047R mutant of PI3K show increased tyrosine phosphorylation of Stat3. This activation of Stat3 is important for the transformation process, because a dominant-negative mutant of Stat3 interferes with PI3K-induced oncogenesis. GDC-0941, a specific inhibitor of PI3K reduces the level of Stat3 phosphorylation. The effect of PI3K on Stat3 appears to be mediated by a member of the Tec kinase family. The Tec kinase inhibitor LFM-A13 blocks Stat3 phosphorylation in H1047R-transformed cells. The Janus kinase inhibitor AG490 and the Src kinase inhibitor Src-1, as well as rapamycin, have no effect on Stat3 phosphorylation in H1047R-transformed cells. The H1047R-transformed cells also release a factor that induces Stat3 phosphorylation in normal cells with possible effects on the cellular microenvironment. In some human tumor cell lines, the enhanced phosphorylation of Stat3 is inhibited by both PI3K and by Tec kinase inhibitors, suggesting that the link between PI3K and Stat3 is significant in human cancer.

• Authors: Jonathan R Hart, Lujian Liao, John R Yates 3rd, Peter K Vogt
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 108 Issue 32 Pg. 13247-52 (Aug 09 2011) ISSN: 1091-6490 [Electronic] United States
• PMID: 21788516 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Amides
• LFM A13
• Mutant Proteins
• Nitriles
• Phosphoinositide-3 Kinase Inhibitors
• STAT3 Transcription Factor
• Class Ia Phosphatidylinositol 3-Kinase

Topics

• Amides (pharmacology)
• Animals
• Cell Line, Tumor
• Cell Transformation, Neoplastic (pathology)
• Class Ia Phosphatidylinositol 3-Kinase (metabolism)
• Fibroblasts (drug effects, metabolism, pathology)
• Genes, Dominant (genetics)
• Humans
• Mice
• Mutant Proteins (metabolism)
• Nitriles (pharmacology)
• Phosphoinositide-3 Kinase Inhibitors
• Phosphorylation (drug effects)
• STAT3 Transcription Factor (metabolism)
• Signal Transduction (drug effects)