Effect of nitric oxide synthase on multiple drug resistance is related to Wnt signaling in non-small cell lung cancer

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.

RETRACTED ARTICLE: A83-01 inhibits TGF-β-induced upregulation of Wnt3 and epithelial to mesenchymal transition in HER2-overexpressing breast cancer cells

“…Wnt/β-catenin signaling pathway is also implicated in playing a critical role in EMT and appears to be associated with resistance to therapeutic treatment in aggressive types of cancer [16, 17, 27–29]. Data from our previous study suggested that activation of Wnt3/β-catenin signaling pathway in HER2-overexpressing breast cancer cells leads to transactivation of EGFR and trastuzumab resistance [18].…”

Epithelial-Mesenchymal Transition and Breast Cancer

“…As a result, β-catenin accumulates in the nucleus, forming the β-catenin/TCF/LEF transcriptional complex, and drives transactivation of Wnt signaling–targeted genes which promote EMT [ 58 , 59 ]. Aberrations in the Wnt signaling pathway have been linked to many human cancers, including breast cancer, and appear to be associated with resistance to therapeutic treatment and aggressive types of cancer [ 60 , 61 , 62 ].…”

Identification of therapeutic targets and mechanisms of tumorigenesis in non-small cell lung cancer using multiple-microarray analysis

“…[ 28 ] TOP2A induces drug resistance via Wnt signaling in NSCLC. [ 29 ] Biagioni et al (2012) showed that CCNA2 affects cell cycle regulation. [ 30 ] KIF20A overexpression confers a malignant phenotype to ovarian tumors by promoting proliferation and inhibiting apoptosis.…”