Linked Life Data

12068000

Source:http://linkedlifedata.com/resource/pubmed/id/12068000

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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
12
pubmed:dateCreated
2002-6-17
pubmed:abstractText
Insulin-like growth factors (IGFs) have mitogenic and antiapoptotic properties and have been implicated in the development of lung cancer. The effects of IGFs are modulated by insulin-like growth factor binding proteins (IGFBPs). This study explored the effects of IGFBP-3 on non-small cell lung cancer (NSCLC) cells after infection with an adenovirus constitutively expressing IGFBP-3 under the control of the cytomegalovirus promoter (Ad5CMV-BP3). We found that IGFs, especially IGF-I, stimulated the growth of NSCLC cells, and Ad5CMV-BP3 suppressed this IGF-I-induced NSCLC cell growth. We also found that the clonogenicity of H1299 cells in soft agar was markedly reduced by Ad5CMV-BP3. Furthermore, direct injection of Ad5CMV-BP3 into H1299 NSCLC xenografts s.c. established in athymic nude mice induced massive destruction of the tumors. Ad5CMV-BP3 did not induce detectable cytotoxicity on normal human bronchial epithelial cells, suggesting therapeutic efficacy of this virus. Ad5CMV-BP3 infection was accompanied by apoptotic cell death in vitro as detected by flow cytometry, DNA fragmentation analysis, and Western blot analysis on the expression of Bcl-2 and on the cleavage of poly(ADP-ribose) polymerase, a substrate of caspase 3. Immunofluorescence confocal microscopy was also used to show the apoptotic effect of Ad5CMV-BP3 in H1299 tumors established in nude mice. These findings indicated that IGFBP-3 was a potent inducer of apoptosis in NSCLC cells in vitro and in vivo. To delineate the underlying mechanism, we examined the effect of IGFBP-3 on Akt/protein kinase B and glycogen synthase kinase-3beta, downstream mediators of the phosphatidylinositol 3-kinase pathway, and on mitogen-activated protein kinase (MAPK), all three of which are activated by IGF-mediated signaling pathways and have important roles in cell survival. IGFBP-3 overexpression inhibited the phosphorylation of Akt and glycogen synthase kinase-3beta and the activity of MAPK. Furthermore, IGF-I rescued the NSCLC cells from serum depletion-induced apoptosis, and this rescue was blocked in Ad5CMV-BP-3-infected H1299 NSCLC cells. Transient transfection with activated Akt or constitutively active MAPK kinase-1, an upstream activator of MAPK, partially blocked IGFBP-3-induced apoptosis of NSCLC cells. These findings suggested that the growth-regulatory effect of IGFBP-3 on NSCLC cells was attributable in part to the inhibition of the IGF-induced survival pathway. These data demonstrate the importance of IGFBP-3 in the regulation of NSCLC cell proliferation, clonogenicity, and tumor growth, suggesting that IGFBP-3 is a target for the treatment of lung cancer and that Ad5CMV-BP3 is a potential therapeutic agent.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0008-5472
pubmed:author
pubmed:issnType
Print
pubmed:day
15
pubmed:volume
62
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
3530-7
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed-meshheading:12068000-Adenoviridae, pubmed-meshheading:12068000-Animals, pubmed-meshheading:12068000-Apoptosis, pubmed-meshheading:12068000-Carcinoma, Non-Small-Cell Lung, pubmed-meshheading:12068000-Cell Division, pubmed-meshheading:12068000-Female, pubmed-meshheading:12068000-Gene Transfer Techniques, pubmed-meshheading:12068000-Humans, pubmed-meshheading:12068000-Insulin-Like Growth Factor Binding Protein 3, pubmed-meshheading:12068000-Lung Neoplasms, pubmed-meshheading:12068000-MAP Kinase Kinase 1, pubmed-meshheading:12068000-MAP Kinase Signaling System, pubmed-meshheading:12068000-Mice, pubmed-meshheading:12068000-Mice, Nude, pubmed-meshheading:12068000-Mitogen-Activated Protein Kinase Kinases, pubmed-meshheading:12068000-Phosphatidylinositol 3-Kinases, pubmed-meshheading:12068000-Protein-Serine-Threonine Kinases, pubmed-meshheading:12068000-Proto-Oncogene Proteins, pubmed-meshheading:12068000-Proto-Oncogene Proteins c-akt
pubmed:year
2002
pubmed:articleTitle
Insulin-like growth factor binding protein-3 inhibits the growth of non-small cell lung cancer.
pubmed:affiliation
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA. hlee@mdanderson.org
pubmed:publicationType
Journal Article