Evidence for phosphatidylinositol 3-kinase-Akt-p7S6K pathway activation and transduction of mitogenic signals by platelet-derived growth factor in meningioma cells.
OBJECTIVE
The intracellular events transducing mitogenic signals from platelet-derived growth factor-beta (PDGFbeta) receptor tyrosine kinases are not precisely known. In this study the authors evaluated whether the phosphatidylinositol 3-kinase (PI3-K)-Akt-p70S6K pathway is expressed in meningiomas, regulates their growth, and transduces mitogenic signals of PDGF-BB.


METHODS
Nine meningioma tumors obtained in humans were evaluated using Western blot analysis for phosphorylated (activated) Akt and phosphorylated p70S6K. Cells cultured from seven of these meningiomas were also screened using Western blot analysis for Akt and for phosphorylated Akt and p70S6K. The authors also evaluated whether PDGF-BB stimulation of meningioma cells was associated with the phosphorylation of Akt and p70S6K known to activate these kinases. In addition, the effects of wortmannin, an inhibitor of P13-K, on proliferation and activation of Akt and p70S6K in meningioma cells stimulated with PDGF-BB were evaluated. Western blots of lysates from meningiomas demonstrated phosphorylated Akt and p70S6K. Treatment with PDGF-BB stimulated phosphorylation of Akt and p70S6K in each meningioma cell culture. Wortmannin (500 and 1000 nM) significantly decreased PDGF-BB stimulation of meningioma cells (p < 0.001) while it reduced Akt and p70S6K phosphorylation but not mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) phosphorylation.


CONCLUSIONS
These findings indicate that Akt and p70S6K are constitutively expressed and activated in meningioma cells and that the PI3-K-Akt-p70S6K pathway may participate in transduction of mitogenic signals in meningiomas independent of the Raf-1-MEK-1-MAPK/ERK cascade.
Johnson
Mahlon D
MD
Department of Pathology, Vanderbilt Medical School, Nashville, Tennessee 37232, USA. mahlon.johnson@mcmail.vanderbilt.edu
Okedli
Evelyn
E
Woodard
Ann
A
Toms
Steven A
SA
Allen
George S
GS
D000328:Adult; D000368:Aged; D000730:Androstadienes / Q000494:pharmacology; D000925:Anticoagulants / Q000494:pharmacology; D000077214:Becaplermin; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D008577:Meningeal Neoplasms / Q000201:enzymology*; D008579:Meningioma / Q000201:enzymology*; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D020574:Proto-Oncogene Proteins c-sis; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*; D013936:Thymidine / Q000493:pharmacokinetics; D014316:Tritium; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology; D000077191:Wortmannin
D000730:Androstadienes; D000925:Anticoagulants; D000077214:Becaplermin; D004791:Enzyme Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D010982:Platelet-Derived Growth Factor; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D020574:Proto-Oncogene Proteins c-sis; D019893:Ribosomal Protein S6 Kinases; D013936:Thymidine; D014316:Tritium; D000077191:Wortmannin; C494918:AKT1 protein, human