Abstract
Our previous study showed that chromosome region maintenance 1 (CRM1), a nuclear export receptor for various cancer-associated "cargo" proteins, was important in regulating lung carcinogenesis in response to a tobacco carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). The objectives of this study are to comprehensively evaluate the significance of CRM1 in lung cancer development and investigate the therapeutic potential of targeting CRM1 for lung cancer treatment using both in vitro and in vivo models. We showed that CRM1 was overexpressed not only in lung tumor tissues from both lung cancer patients and mice treated with NNK but also in NNK-transformed BEAS-2B human bronchial epithelial cells. Furthermore, stable overexpression of CRM1 in BEAS-2B cells by plasmid vector transfection led to malignant cellular transformation. Moreover, a decreased CRM1 expression level in A549 cells by short hairpin siRNA transfection led to a decreased tumorigenic activity both in vitro and in nude mice, suggesting the potential to target CRM1 for lung cancer treatment. Indeed, we showed that the cytotoxic effects of cisplatin on A549 cells with CRM1 down-regulated by short hairpin siRNA were significantly increased, compared with A549 cells, and the cytotoxic effects of cisplatin became further enhanced when the drug was used in combination with leptomycin B, a CRM1 inhibitor, in both in vitro and in vivo models. Cancer target genes were significantly involved in these processes. These data suggest that CRM1 plays an important role in lung carcinogenesis and provides a novel target for lung cancer adjuvant therapy.
MeSH terms
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Adenocarcinoma / chemistry
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Adenocarcinoma / genetics*
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Adult
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Aged
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Aged, 80 and over
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Animals
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Antibiotics, Antineoplastic / pharmacology
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Antineoplastic Agents / pharmacology
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Carcinoma, Non-Small-Cell Lung / chemistry
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Carcinoma, Non-Small-Cell Lung / genetics*
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Carcinoma, Squamous Cell / chemistry
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Carcinoma, Squamous Cell / genetics*
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Cell Cycle Checkpoints / drug effects
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Cell Survival / drug effects
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Cell Transformation, Neoplastic / drug effects*
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Cells, Cultured
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Cisplatin / pharmacology
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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Exportin 1 Protein
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Fatty Acids, Unsaturated / pharmacology
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Female
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Gene Expression / drug effects
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Gene Silencing
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Humans
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Inhibitor of Apoptosis Proteins / metabolism
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Karyopherins / analysis*
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Karyopherins / genetics*
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Karyopherins / metabolism
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Lung / chemistry
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Lung Neoplasms / chemistry
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Lung Neoplasms / genetics*
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology
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Male
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Mice
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Mice, Nude
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Middle Aged
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Nitrosamines / pharmacology
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Phosphorylation
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Poly (ADP-Ribose) Polymerase-1
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Poly(ADP-ribose) Polymerases / metabolism
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RNA, Messenger / metabolism
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Receptors, Cytoplasmic and Nuclear / analysis*
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Receptors, Cytoplasmic and Nuclear / genetics*
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Receptors, Cytoplasmic and Nuclear / metabolism
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Smoking
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Survivin
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Transfection
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Tumor Stem Cell Assay
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Tumor Suppressor Protein p53 / metabolism
Substances
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Antibiotics, Antineoplastic
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Antineoplastic Agents
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BIRC5 protein, human
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CDKN1A protein, human
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Cyclin-Dependent Kinase Inhibitor p21
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Fatty Acids, Unsaturated
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Inhibitor of Apoptosis Proteins
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Karyopherins
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Nitrosamines
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RNA, Messenger
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Receptors, Cytoplasmic and Nuclear
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Survivin
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Tumor Suppressor Protein p53
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4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone
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PARP1 protein, human
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Poly (ADP-Ribose) Polymerase-1
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Poly(ADP-ribose) Polymerases
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Cisplatin
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leptomycin B