PTEN and phosphatidylinositol 3'-kinase inhibitors up-regulate p53 and block tumor-induced angiogenesis: evidence for an effect on the tumor and endothelial compartment.
Previous work from our laboratory demonstrated that PTEN regulates tumor-induced angiogenesis and thrombospondin 1 expression in malignant glioma. Herein, we demonstrated the first evidence that the systemic administration of a phosphatidylinositol 3'-kinase (PI3K) inhibitor (LY294002) has antitumor and antiangiogenic activity in vivo. We show that PTEN reconstitution diminished phosphorylation of AKT, induced the transactivation of p53 (7.5-fold induction) and increased the expression of p53 target genes, p21(waf-1) and insulin-like growth factor binding protein 3 in glioma cells. PTEN and LY294002 induced p53 activity in human brain endothelial cells, suggesting that PTEN and PI3K pathways can suppress the progression of cancer through direct actions on tumor and endothelial cells. The capacity of PTEN and LY294002 to inhibit U87MG or U373MG glioma growth was tested in an ectopic skin and orthotopic brain tumor model. LY294002 inhibited glioma tumor growth in vivo, induced tumor regression, decreased the incidence of brain tumors, and blocked the tumor-induced angiogenic response of U87MG cells in vivo. These data provide evidence that both PTEN and PI3K inhibitors regulate p53 function and display in vivo antiangiogenic and antitumor activity. These results provide evidence that the two tumor suppressor genes, PTEN and p53, act together to block tumor progression in vivo. Our data provide the first preclinical evidence for the in vivo efficacy for LY294002 in the treatment of malignant gliomas.
Su
Jing Dong
JD
Section of Hematology/Oncology, Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46204, USA.
Mayo
Lindsey D
LD
Donner
David B
DB
Durden
Donald L
DL
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000098:blood supply / Q000473:pathology; D002455:Cell Division; D002460:Cell Line; D002470:Cell Survival; D002560:Cerebrovascular Circulation; D002867:Chromones / Q000627:therapeutic use*; D004730:Endothelium, Vascular / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D016147:Genes, Tumor Suppressor / Q000187:drug effects*; D016158:Genes, p53 / Q000187:drug effects; D005910:Glioma / Q000098:blood supply / Q000473:pathology; D006801:Humans; D007700:Kinetics; D009025:Morpholines / Q000627:therapeutic use*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D051059:PTEN Phosphohydrolase; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors*
D020533:Angiogenesis Inhibitors; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D025521:Tumor Suppressor Proteins; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human