Irinotecan induces steroid and xenobiotic receptor (SXR) signaling to detoxification pathway in colon cancer cells

Abstract

BackgroundResistance to chemotherapy remains one of the principle obstacles to the treatment of colon cancer. In order to identify the molecular mechanism of this resistance, we investigated the role of the steroid and xenobiotic receptor (SXR) in the induction of drug resistance. Indeed, this nuclear receptor plays an important role in response to xenobiotics through the upregulation of detoxification genes. Following drug treatments, SXR is activated and interacts with the retinoid X receptor (RXR) to induce expression of some genes involved in drug metabolism such as phase I enzyme (like CYP), phase II enzymes (like UGT) and transporters (e.g. MDR1).ResultsIn this study, we have shown that endogenous SXR is activated in response to SN-38, the active metabolite of the anticancer drug irinotecan, in human colon cancer cell lines. We have found that endogenous SXR translocates into the nucleus and associates with RXR upon SN-38 treatment. Using ChIP, we have demonstrated that endogenous SXR, following its activation, binds to the native promoter of the CYP3A4 gene to induce its expression. RNA interference experiments confirmed SXR involvement in CYP3A4 overexpression and permitted us to identify CYP3A5 and MRP2 transporter as SXR target genes. As a consequence, cells overexpressing SXR were found to be less sensitive to irinotecan treatment.ConclusionsAltogether, these results suggest that the SXR pathway is involved in colon cancer irinotecan resistance in colon cancer cell line via the upregulation of select detoxification genes.

Epirubicin Upregulates UDP Glucuronosyltransferase 2B7 Expression in Liver Cancer Cells via the p53 Pathway

“…The active metabolite SN-38 (7-ethyl-10-hydroxylcamptothecin) of irinotecan is primarily inactivated by UGT1A1. Studies have shown that overexpression of UGT1A1 in a lung cancer cell line (PC-7/CPT) (Oguri et al, 2004) or induction of UGT1A1 by SN-38 in colon (LS180) and liver (HepG2) cancer cell lines is associated with irinotecan resistance (Basseville et al, 2011). The induction of UGT2B7 by its substrate EPI described in the present study may represent a new example of this type of regulation.…”

CYP3A4 Expression in Breast Cancer and its Association with Risk Factors in Mexican Women

“…In recent years have been described several genetic polymorphisms that affect the expression of this gene (Chu and Fyles, 2007). CYP3A4 protein expression has been observed in cancer tissues (Takahara et al, 2011;Weiss and Haefeli, 2011) due the induction of different kind of substances, resulting in an increase in transcription and expression of CYP3A4 (Basseville et al, 2011).…”

Anticancer Drug Metabolism: Chemotherapy Resistance and New Therapeutic Approaches

“…Additionally, CYP3A4 phenotype, as assessed by midazolam clearance, is significantly associated with irinotecan pharmacokinetic (Mathijssen et al, 2004). More recently, a study suggested that the Pregnane X-Receptor (PXR) pathway is also involved in irinotecan resistance in colon cancer cell line via the upregulation of drug-metabolizing genes such as CYP3A4 (Basseville et al, 2011).…”