The tumor suppressor PTEN positively regulates macroautophagy by inhibiting the phosphatidylinositol 3-kinase/protein kinase B pathway

The tumor suppressor PTEN is a dual protein and phosphoinositide phosphatas e that negatively controls the phosphatidylinositol (PI) 3-kinase/protein k inase B (Akt/PKB) signaling pathway. Interleukin-13 via the activation of t he class I PI 3-kinase has been shown to inhibit the macroautophagic pathwa y in the human colon cancer HT-29 cells. Here we demonstrate that the wild- type PTEN is expressed in this cell line. Its overexpression directed by an inducible promoter counteracts the interleukin-13 down-regulation of macro autophagy. This effect was dependent upon the phosphoinositide phosphatase activity of PTEN as determined by using the mutant G129E, which has only pr otein phosphatase activity. The role of Akt/PKB in the signaling control of interleukin-13-dependent macroautophagy was investigated by expressing a c onstitutively active form of the kinase ((PKB)-P-Myr). Under these conditio ns a dramatic inhibition of macroautophagy was observed. By contrast a high rate of autophagy was observed in cells expressing a dominant negative for m of PKB. These data demonstrate that the signaling control of macroautopha gy overlaps with the well known PI 3-kinase/PKB survival pathway and that t he loss of PTEN function in cancer cells inhibits a major catabolic pathway .