Co-expression of pregnane X receptor and ATP-binding cassette sub-family B member 1 in peripheral blood: A prospective indicator for drug resistance prediction in non-small cell lung cancer

Abstract

The aim of the present study was to investigate the protein expression profiling of pregnane X receptor (PXR) and ATP-binding cassette sub-family B member 1 (ABCB1; also known as MDR1 or P-gp), present in the peripheral blood mononuclear cells (PBMCs) and cancerous tissues of cases of non-small cell lung cancer (NSCLC). Furthermore, the study aimed to assess the feasibility of predicting drug resistance through the medium of PBMCs. Of the subjects included in the study, 37 were histopathologically diagnosed with NSCLC and 17 were control patients without cancer. ThinPrep liquid-based smears with cytosine were applied in the examination of the PBMCs and proved quite effective in preserving the morphology and surface antigens of the lymphocytes. Measurements of expression levels in the PBMCs and cancerous tissues were obtained by immunohistochemical means. The results showed that, with the exception of the selective PXR expression in the normal lung tissues, the two types of proteins existed extensively throughout the PBMCs, normal tissues and tumors. Among the cancer patients, prior to chemotherapy, a significant rise in ABCB1 expression could be observed in the PBMCs, together with a similar rise in ABCB1 and PXR expression in the tumor specimens. Marked upregulation of the two proteins was detected in the PBMCs following 1 cycle of first-line chemotherapy. ABCB1 expression, correlated with PXR, persisted mostly in the PBMCs and tissue samples. When bound to and activated by ligands, PXR translocates from the cytoplasm to the nucleus of the cells. PXR subsequently binds to its DNA response elements as a heterodimer with the retinoid X receptor. A PXR translocation of moderate or low differentiation was identified in 3 cases of adenocarcinoma, which were co-expressing the two genes in the PBMCs prior to chemotherapy. During follow-up visits, tumor recurrence was observed within 3 months in 5 cases, which were characterized by PXR translocation. These findings indicate that the combined expression of PXR and ABCB1 in PBMCs may be used as a prospective indicator in diagnosis prior to histopathological diagnosis, and therefore may function as a novel biomarker for the prediction of drug resistance.

Impact of a diet and activity health promotion intervention on regional patterns of DNA methylation

“…In the current study, we observed a decrease in methylation following the MBC2 intervention, which may indicate an upregulation of DUSP5P1 and tumor suppression. Kong et al found that, among non-small cell lung cancer cases (n = 37) compared to controls (n = 17), NR1I2 (aka PXR) expression was significantly higher among non-small cell lung cancer tumors compared to peripheral blood mononuclear cells [47]. We also observed that methylation increased in this region following MBC2, which may indicate that a healthier lifestyle downregulates the protein in immune cells.…”

Pregnane X receptors regulate CYP2C8 and P‐glycoprotein to impact on the resistance of NSCLC cells to Taxol

“…Likewise, in previous studies, compared with normal tissues like bronchial epithelium and alveolar tissues in the normal lung, the neoplastic tissues such as NSCLC cells expressed the PXR at a significantly higher level, which suggested that PXR selectively participated in the development of tumorigenesis . Furthermore, PXR participates in resistance to chemotherapeutics by regulating the expression of some enzymes or transports that are associated with the metabolism of the drug . Therefore, PXR can be used to predict the potential risk of drug resistance in NSCLC patients.…”

“…The collected cells were centrifuged and the supernatant was extracted by ethyl acetate. The freeze drying powders were then dissolved in 200 μL methyl alcohol/water solutions (65: 35, v/v). Taxol and 6′-hydroxyl Taxol were analyzed by high-performance liquid chromatography (HPLC) assay (injection volume: 20 μL, analytical column: C18, eluent: methyl alcohol/water (65:35, v/v), flow rate: 1 mL/min).…”

Pregnane X Receptor and Cancer: Context-Specificity is Key

“…Like colon carcinogenesis, a PXR polymorphism in the 3′ UTR predicts for low PXR levels and increased lung cancer risk in smokers from China (Zhang et al, 2014a). Very recently, PXR was proposed to be a novel biomarker for predicting drug resistance in non-small cell lung cancer patients (Kong et al, 2016). …”