Abstract
Multiple drug resistance (MDR) is considered a major challenge in the clinical treatment of non-small cell lung cancer (NSCLC). Both nitric oxide synthase (iNOS) and Wnt signaling pathway participate in the regulation of drug resistance, but the interaction between them remains unclear. In the present study, we detected the activation of Wnt/β-catenin signaling in iNOS-induced drug-resistant lung cancer cells, and compared the effect of canonical and noncanonical Wnt pathway on the level of iNOS. Moreover, we investigated the expression of Wnt/β-catenin signaling downstream factors and its main inhibitors. The results indicated iNOS-induced drug resistance was possibly mediated by glutathione S-transferase-π (GST-π) and topoisomerase IIα (TOPO IIα), but not P-glycoprotein (P-gp), and this process was closely associated with the activation of canonical Wnt/β-catenin signaling, but less with noncanonical pathways. The mechanism of iNOS promoting Wnt/β-catenin pathway was mainly dependent on the inverse regulation of Dickkopf-1 (DKK-1) and secreted frizzled-related protein-1 (SFRP-1). Clarifying the relationship between iNOS and Wnt signaling may provide insight into a better understanding of the mechanism of drug resistance development in NSCLC.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antigens, Neoplasm / genetics
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Antigens, Neoplasm / metabolism
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Carcinoma, Non-Small-Cell Lung / genetics*
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Carcinoma, Non-Small-Cell Lung / metabolism
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Cell Line, Tumor
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DNA Topoisomerases, Type II / genetics
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DNA Topoisomerases, Type II / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Drug Resistance, Multiple / genetics*
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Drug Resistance, Neoplasm / genetics*
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Glutathione Transferase / genetics
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Glutathione Transferase / metabolism
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Humans
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism
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Lung Neoplasms / genetics*
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Lung Neoplasms / metabolism
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Nitric Oxide Synthase Type II / genetics*
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Nitric Oxide Synthase Type II / metabolism
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RNA, Messenger / genetics*
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Wnt Proteins / genetics
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Wnt Proteins / metabolism
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Wnt Signaling Pathway / genetics*
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beta Catenin / genetics
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beta Catenin / metabolism
Substances
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Antigens, Neoplasm
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DKK1 protein, human
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DNA-Binding Proteins
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Intercellular Signaling Peptides and Proteins
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Membrane Proteins
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RNA, Messenger
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SFRP1 protein, human
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Wnt Proteins
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beta Catenin
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NOS2 protein, human
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Nitric Oxide Synthase Type II
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Glutathione Transferase
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DNA Topoisomerases, Type II