title: Rapamycin inhibits Akt-mediated oncogenic transformation and tumor growth.
abstract: 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.
authors.affiliation: Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA.
authors.forename: Xuesong
authors.initials: X
authors.lastname: Liu
authors.forename: Jessica
authors.initials: J
authors.lastname: Powlas
authors.forename: Yan
authors.initials: Y
authors.lastname: Shi
authors.forename: Anatol X
authors.initials: AX
authors.lastname: Oleksijew
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Shoemaker
authors.forename: Ron
authors.initials: R
authors.lastname: De Jong
authors.forename: Tilman
authors.initials: T
authors.lastname: Oltersdorf
authors.forename: Vincent L
authors.initials: VL
authors.lastname: Giranda
authors.forename: Yan
authors.initials: Y
authors.lastname: Luo
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D007527:Isoenzymes; D011518:Proto-Oncogene Proteins; C494922:Akt2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D020123:Sirolimus