Bone morphogenetic protein-2-induced transformation involves the activation of mammalian target of rapamycin.
Bone morphogenetic protein-2 (BMP-2) is an evolutionary conserved protein that is essential for embryonic development. BMP-2 is highly expressed in approximately 98% of human lung carcinomas with little expression in normal lung tissues. BMP-2 has been shown to enhance mobility, invasiveness, and metastasis of cancer cell lines. During development, BMP-2 induces the proto-oncogene phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway to regulate stem cell differentiation. We show that BMP-2 induces the phosphorylation of mTOR in A549 and H1299 lung cancer cell lines, which is attenuated by the PI3K antagonists LY-294002 and wortmannin. p70S6 kinase, which is a direct downstream target of mTOR, is also regulated by BMP-2 in lung cancer cell lines. We find that BMP-2 induces cyclin E in A549 and H1299 cells, which is mediated by the PI3K/mTOR signaling pathway. The regulation of cyclin E by BMP-2 occurs through a Smad 1/5-independent mechanism. Forced expression of BMP-2 in A549 cells (A549/BMP-2) induces transformation as shown by an increase in foci formation. The mTOR antagonist, rapamycin, prevented foci formation of the A549/BMP-2 cells. This study provides evidence that BMP-2-mediated transformation of lung cancer cells involves the activation of the PI3K/mTOR signaling pathway.
Langenfeld
Elaine M
EM
Department of Surgery, Division of Thoracic Surgery, University of Medicine and Dentistry, New Jersey Robert Wood Johnson Medical School, NJ 08903-0019, USA.
Kong
Yingxin
Y
Langenfeld
John
J
D000730:Androstadienes / Q000494:pharmacology; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000502:physiology*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism*; D002867:Chromones / Q000494:pharmacology; D019927:Cyclin E / Q000378:metabolism; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology; D051785:Smad Proteins / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D016212:Transforming Growth Factor beta / Q000502:physiology*; D015854:Up-Regulation; D000077191:Wortmannin
D000730:Androstadienes; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D002867:Chromones; D019927:Cyclin E; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases; D000090063:Proto-Oncogene Mas; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020123:Sirolimus; D051785:Smad Proteins; D058570:TOR Serine-Threonine Kinases; D016212:Transforming Growth Factor beta; D000077191:Wortmannin; C525718:BMP2 protein, human; C000715470:MAS1 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C546842:MTOR protein, human