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.
Liu
Xuesong
X
Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA.
Powlas
Jessica
J
Shi
Yan
Y
Oleksijew
Anatol X
AX
Shoemaker
Alexander R
AR
De Jong
Ron
R
Oltersdorf
Tilman
T
Giranda
Vincent L
VL
Luo
Yan
Y
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
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