Abstract
BackgroundCisplatin is a first-line drug for the treatment of human non-small cell lung cancer (NSCLC); however, the majority of patients will develop drug resistance after treatment. In order to overcome cisplatin resistance, it is important to understand the mechanisms underlying the resistance.MethodsA gene microarray was used to screen for genes related to cisplatin resistance in NSCLC cell lines. Subsequently, the correlation between the HDAC, RXR and HtrA1 genes, in NSCLC, were verified using gene manipulation. Immunohistochemical staining was used to detect HDAC, RXR and HtrA1 expression in NSCLC specimens. Proliferation, migration and invasion assays were performed in vitro and in vivo to determine the role of the HDAC/RXR/HtrA1 signaling axis in cisplatin resistance, and luciferase reporter analysis and ChIP assays were performed to ascertain the mechanisms by which HDAC and RXR regulate the expression of HtrA1. Furthermore, in vitro and in vivo experiments were conducted in NSCLC cisplatin-resistant NSCLC to elucidate the effect of the low molecular weight compound, DW22, which targets the NSCLC cisplatin resistance HDAC/RXR/HtrA1 signaling pathway.ResultsHtrA1 was identified as a cisplatin resistance-related gene in NSCLC cells. The regulation of HtrA1 by HDAC and RXR significantly decreased the efficacy of cisplatin in NSCLC cells resistant to cisplatin. Immunohistochemistry results showed a negative relationship between HDAC1 and HtrA1, and a positive relationship between RXRα and HtrA1 in NSCLC patients’ tissues. Notably, the expression of HDAC1 and HtrA1 can be considered as biomarkers for the efficacy of platinum-based drugs and prognosis in NSCLC patients. Mechanistically, the heterodimers of the nuclear receptor RXR, in combination with the enzyme, HDAC, regulate the transcription of HtrA1 in NSCLC cells. The rescue of HtrA1 expression by dual targeting of HDAC and RXR with the compound, DW22, significantly inhibited the proliferation, migration and invasion of NSCLC cells resistant to cisplatin, and induced NSCLC cell apoptosis.ConclusionOur results indicate that HtrA1, a cisplatin resistance-related gene, is synergistically regulated by HDAC and RXR in NSCLC. Targeting the HDAC/RXR/HtrA1 signaling axis can rescue HtrA1 expression and reverse cisplatin resistance in NSCLC.
Highlights
Cisplatin is a first-line drug for the treatment of human non-small cell lung cancer (NSCLC); the majority of patients will develop drug resistance after treatment
Our results indicate that high temperature requirement factor serine peptidase 1 (HtrA1), a cisplatin resistance-related gene, is synergistically regulated by histone deacetylation enzyme (HDAC) and Retinoid X receptor (RXR) in NSCLC
The above results indicate that HtrA1 is downregulated in CDDP resistant NSCLC cells, and the nuclear receptor RXR and the epigenetic regulatory enzyme HDAC may be involved in the regulation of HtrA1
Summary
Cisplatin is a first-line drug for the treatment of human non-small cell lung cancer (NSCLC); the majority of patients will develop drug resistance after treatment. It has been reported that CDDP resistance in NSCLC can result from alterations in: 1) alteration of influx and efflux of drugs from the cancer cells, such as copper transporter CTR1 [10, 11], P-gp [12] and other transporters [13, 14]; 2) enhancing the capacity for DNA repair, for instance, the upregulation of nucleotide excision repair related protein ERCC1 [15]; 3) downregulation of the expression of apoptosis proteins, including Bcl-2 and Bak [7, 16, 17]; 4) the change of important molecular signal pathways [11, 18, 19], such as IGF and MAPK pathways. Socinski MA et al reported targeting components in the tumor microenvironment, such as immune system treatment, is associated with better survival outcomes [21]
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