No abstract

The PTEN͞MMAC1 phosphatase is a tumor suppressor gene implicated in a wide range of human cancers. Here we provide biochemical and functional evidence that PTEN͞MMAC1 acts a negative regulator of the phosphoinositide 3-kinase (PI3-kinase)͞Akt pathway. PTEN͞MMAC1 impairs activation of endogenous Akt in cells and inhibits phosphorylation of 4E-BP1, a downstream target of the PI3-kinase͞Akt pathway involved in protein translation, whereas a catalytically inactive, dominant negative PTEN͞MMAC1 mutant enhances 4E-BP1 phosphorylation. In addition, PTEN͞MMAC1 represses gene expression in a manner that is rescued by Akt but not PI3-kinase. Finally, higher levels of Akt activation are observed in human prostate cancer cell lines and xenografts lacking PTEN͞MMAC1 expression when compared with PTEN͞MMAC1-positive prostate tumors or normal prostate tissue. Because constitutive activation of either PI3-kinase or Akt is known to induce cellular transformation, an increase in the activation of this pathway caused by mutations in PTEN͞MMAC1 provides a potential mechanism for its tumor suppressor function.

PTEN phosphatase acts as a tumor suppressor by negatively regulating the phosphoinositide 3-kinase (PI3K) signaling pathway. It is unclear which downstream components of this pathway are necessary for oncogenic transformation. In this report we show that transformed cells of PTEN ؉/؊ mice have elevated levels of phosphorylated Akt and activated p70͞S6 kinase associated with an increase in proliferation. Pharmacological inactivation of mTOR͞ RAFT͞FRAP reduced neoplastic proliferation, tumor size, and p70͞S6 kinase activity, but did not affect the status of Akt. These data suggest that p70͞S6K and possibly other targets of mTOR contribute significantly to tumor development and that inhibition of these proteins may be therapeutic for cancer patients with deranged PI3K signaling.