Rapamycin Inhibits Akt-Mediated Oncogenic Transformation and Tumor Growth

• Published in: Anticancer research 2004-09, Vol.24 (5A), p.2697-2704
• Main Authors: Liu, Xuesong, Powlas, Jessica, Shi, Yan, Oleksijew, Anatol X, Shoemaker, Alexander R, De Jong, Ron, Oltersdorf, Tilman, Giranda, Vincent L, Luo, Yan
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Antibiotics, Antineoplastic - pharmacology; Biological and medical sciences; Cell Division - drug effects; Cell Transformation, Neoplastic - drug effects; Isoenzymes - antagonists & inhibitors; Isoenzymes - biosynthesis; Isoenzymes - genetics; Male; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - physiology; Medical sciences; Mice; Mice, SCID; Molecular Sequence Data; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - enzymology; Neoplasms, Experimental - pathology; NIH 3T3 Cells; p38 Mitogen-Activated Protein Kinases - metabolism; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - biosynthesis; Protein-Serine-Threonine Kinases - genetics; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - biosynthesis; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins c-akt; Sirolimus - pharmacology; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0250-7005; 1791-7530

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.