Rapamycin inhibits Akt-mediated oncogenic transformation and tumor growth.

Akt is a serine/threonine kinase that plays a critical role in cell survival and proliferation. Three isoforms of Akt have been identified and have been shown to be up-regulated in human malignancies. We examined the requirement of these pathways for Akt transformation. We generated NIH-3T3 cells over-expressing constitutively active Myr-Akt1 (3T3-Akt1 cells) or Myr-Akt2 (3T3-Akt2 cells). These cells are able to form colonies in soft-agar and 3T3-Akt1 cells formed tumors in SCID mice. Rapamycin efficiently inhibited the activation of the mTOR-p70S6K pathway and the anchorage-independent growth of both 3T3-Akt cells, demonstrating the importance of the mTOR-p70S6K pathway for transformation by Akt1 as well as by Akt2. Moreover, rapamycin dramatically inhibited the tumor formation by 3T3-Akt1 cells in SCID mice. Thus, we demonstrated the importance of mTOR-p70S6 kinase pathway in the transformation by Akt, both in tissue-cultured cells and in animal tumor models. In contrast, neither the MAPK pathway nor the p38 MAPK pathway is required for Akt-dependent transformation of NIH3T3 cells.