Abstract
The neurotrophin family of growth factors and their receptors support the survival of several neuronal and non-neuronal cell populations during embryonic development and adult life. Neurotrophins are also involved in malignant transformation. To seek the role of neurotrophin signaling in human lung cancer we studied the expression of neurotrophin receptors in human lung adenocarcinomas and investigated the effect of the neurotrophin receptor inhibitor K252a in A549 cell survival and colony formation ability in soft agar. We showed that human lung adenocarcinomas express TrkA and TrkB, but not TrkC; A549 cells, derived from a human lung adenocarcinoma, express mRNA transcripts encoding nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), TrkA, TrkB, and p75, and high protein levels of TrkA and TrkB. Stimulation of cells using NGF or BDNF activates the anti-apoptotic protein Akt. Interestingly, inhibition of neurotrophin receptor signaling using K252a prevents Akt activation in response to NGF or BDNF, induces apoptotic cell death, and diminishes the ability of A549 cells to growth in soft agar. The data suggest that neurotrophin signaling inhibition using k252a may be a valid therapy to treat patients with lung adenocarcinomas.
MeSH terms
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Adenocarcinoma / enzymology*
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Adenocarcinoma / genetics
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Adenocarcinoma / pathology*
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Adult
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Apoptosis / drug effects
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Carbazoles / pharmacology*
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Caspase 3 / metabolism
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Cell Line, Tumor
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Dose-Response Relationship, Drug
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Enzyme Activation / drug effects
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Female
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Indole Alkaloids
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Lung Neoplasms / enzymology*
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Lung Neoplasms / genetics
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Lung Neoplasms / pathology*
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Male
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Middle Aged
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Nerve Growth Factors / genetics
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Nerve Growth Factors / metabolism
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Phosphorylation / drug effects
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Phosphoserine / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
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Receptor Protein-Tyrosine Kinases / genetics
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Receptor Protein-Tyrosine Kinases / metabolism
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Receptor, trkA / antagonists & inhibitors
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Receptor, trkA / genetics
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Receptor, trkA / metabolism
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Receptor, trkB / antagonists & inhibitors
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Receptor, trkB / genetics
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Receptor, trkB / metabolism
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Receptor, trkC / antagonists & inhibitors
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Receptor, trkC / genetics
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Receptor, trkC / metabolism
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Tumor Stem Cell Assay
Substances
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Carbazoles
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Indole Alkaloids
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Nerve Growth Factors
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RNA, Messenger
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Phosphoserine
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staurosporine aglycone
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Receptor Protein-Tyrosine Kinases
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Receptor, trkA
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Receptor, trkB
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Receptor, trkC
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Proto-Oncogene Proteins c-akt
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Caspase 3