Abstract
Fragile histidine triad (FHIT) loss by the two-hit mechanism of loss of heterozygosity and promoter hypermethylation commonly occurrs in non-small cell lung cancer (NSCLC) and may confer cisplatin resistance in NSCLC cells. However, the underlying mechanisms of FHIT loss in cisplatin resistance and the response to cisplatin-based chemotherapy in NSCLC patients have not yet been reported. In the present study, inhibition concentration of 50% cell viability induced by cisplatin (IC50) and soft agar growth and invasion capability were increased and decreased in FHIT-knockdown and -overexpressing cells, respectively. Mechanistically, Slug transcription is upregulated by AKT/NF-κB activation due to FHIT loss and, in turn, Slug suppresses PUMA expression; this decrease of PUMA by FHIT loss is responsible for cisplatin resistance. In addition, cisplatin resistance due to FHIT loss can be conquered by AKT inhibitor-perifosine in xenograft tumors. Among NSCLC patients, low FHIT, high p-AKT, high Slug and low PUMA were correlated with shorter overall survival, relapse-free survival and poorer response to cisplatin-based chemotherapy. Therefore, the AKT inhibitor perifosine might potentially overcome the resistance to cisplatin-based chemotherapy in NSCLC patients with low-FHIT tumors, and consequently improve the outcome.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acid Anhydride Hydrolases / 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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Antineoplastic Agents / therapeutic use
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Apoptosis / genetics
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism
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Carcinoma, Non-Small-Cell Lung / drug therapy
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Carcinoma, Non-Small-Cell Lung / genetics
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Carcinoma, Non-Small-Cell Lung / mortality
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Cisplatin / therapeutic use
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Drug Resistance, Neoplasm / genetics*
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Female
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Humans
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Lung Neoplasms / drug therapy
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Lung Neoplasms / genetics
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Lung Neoplasms / mortality
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Middle Aged
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Neoplasm Proteins / genetics*
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Neoplasm Transplantation
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Nitriles / pharmacology
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Phosphorylcholine / analogs & derivatives
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Phosphorylcholine / pharmacology
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / metabolism*
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RNA Interference
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RNA, Small Interfering
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Snail Family Transcription Factors
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Sulfones / pharmacology
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Transcription Factor RelA / antagonists & inhibitors
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Transcription Factor RelA / metabolism*
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transplantation, Heterologous
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Treatment Outcome
Substances
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3-(4-methylphenylsulfonyl)-2-propenenitrile
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Antineoplastic Agents
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Apoptosis Regulatory Proteins
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BBC3 protein, human
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Neoplasm Proteins
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Nitriles
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Proto-Oncogene Proteins
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RNA, Small Interfering
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SNAI1 protein, human
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Snai2 protein, mouse
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Snail Family Transcription Factors
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Sulfones
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Transcription Factor RelA
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Transcription Factors
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fragile histidine triad protein
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Phosphorylcholine
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perifosine
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Proto-Oncogene Proteins c-akt
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Acid Anhydride Hydrolases
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Cisplatin