PTEN and phosphatidylinositol 3′-kinase inhibitors up-regulate p53 and block tumor-induced angiogenesis

Evidence for an effect on the tumor and endothelial compartment

Jing Dong Su, Lindsey D. Mayo, David B. Donner, Donald L Durden

Research output: Contribution to journalArticle

110 Citations (Scopus)

Abstract

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, p21waf-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.

Original languageEnglish (US)
Pages (from-to)3585-3592
Number of pages8
JournalCancer Research
Volume63
Issue number13
StatePublished - Jul 1 2003

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Phosphatidylinositol 3-Kinase
Angiogenesis Inducing Agents
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Up-Regulation
Glioma
Neoplasms
Brain Neoplasms
Endothelial Cells
Thrombospondin 1
Insulin-Like Growth Factor Binding Protein 3
p53 Genes
Growth
Tumor Suppressor Genes
Human Activities
Transcriptional Activation
Phosphorylation
Skin
Incidence
Brain

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

PTEN and phosphatidylinositol 3′-kinase inhibitors up-regulate p53 and block tumor-induced angiogenesis : Evidence for an effect on the tumor and endothelial compartment. / Su, Jing Dong; Mayo, Lindsey D.; Donner, David B.; Durden, Donald L.

In: Cancer Research, Vol. 63, No. 13, 01.07.2003, p. 3585-3592.

Research output: Contribution to journalArticle

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