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    Pregnane x Receptor (PXR) expression in colorectal cancer cells restricts irinotecan chemosensitivity through enhanced SN-38 glucuronidation

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    Author
    Raynal, C; Pascussi, J-M; Legueline, G; Breuker, C; Kantar, J; Lallemant, B; Poujol, S; Bonnans, C; Joubert, D; Hollande, F; ...
    Date
    2010
    Source Title
    MOLECULAR CANCER
    Publisher
    BMC
    University of Melbourne Author/s
    Hollande, Frederic
    Affiliation
    Pathology
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Raynal, C., Pascussi, J. -M., Legueline, G., Breuker, C., Kantar, J., Lallemant, B., Poujol, S., Bonnans, C., Joubert, D., Hollande, F., Lumbroso, S., Brouillet, J. -P. & Evrard, A. (2010). Pregnane x Receptor (PXR) expression in colorectal cancer cells restricts irinotecan chemosensitivity through enhanced SN-38 glucuronidation. MOLECULAR CANCER, 9 (1), https://doi.org/10.1186/1476-4598-9-46.
    Access Status
    Access this item via the Open Access location
    URI
    http://hdl.handle.net/11343/33321
    DOI
    10.1186/1476-4598-9-46
    Open Access at PMC
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2838814
    Description

    C1 - Journal Articles Refereed

    Abstract
    Clinical efficacy of chemotherapy in colorectal cancer is subjected to broad inter-individual variations leading to the inability to predict outcome and toxicity. The topoisomerase I inhibitor irinotecan (CPT-11) is worldwide approved for the treatment of metastatic colorectal cancer and undergoes extensive peripheral and tumoral metabolism. PXR is a xenoreceptor activated by many drugs and environmental compounds regulating the expression of drug metabolism and transport genes in detoxification organs such as liver and gastrointestinal tract. Considering the metabolic pathway of irinotecan and the tissue distribution of Pregnane x Receptor (PXR), we hypothesized that PXR could play a key role in colon cancer cell response to irinotecan.PXR mRNA expression was quantified by RT-quantitative PCR in a panel of 14 colon tumor samples and their matched normal tissues. PXR expression was modulated in human colorectal cancer cells LS174T, SW480 and SW620 by transfection and siRNA strategies. Cellular response to irinotecan and its active metabolic SN38 was assessed by cell viability assays, HPLC metabolic profiles and mRNA quantification of PXR target genes. We showed that PXR was strongly expressed in colon tumor samples and displayed a great variability of expression. Expression of hPXR in human colorectal cancer cells led to a marked chemoresistance to the active metabolite SN38 correlated with PXR expression level. Metabolic profiles of SN38 showed a strong enhancement of SN38 glucuronidation to the inactive SN38G metabolite in PXR-expressing cells, correlated with an increase of UDPglucuronosyl transferases UGT1A1, UGT1A9 and UGT1A10 mRNAs. Inhibition of PXR expression by lentivirus-mediated shRNA, led to SN38 chemoresistance reversion concomitantly to a decrease of UGT1A1 expression and SN38 glucuronidation. Similarly, PXR mRNA expression levels correlated to UGT1A subfamily expression in human colon tumor biopsies.Our results demonstrate that tumoral metabolism of SN38 is affected by PXR and point to potential therapeutic significance of PXR quantification in the prediction of irinotecan response. Furthermore, our observations are pharmacologically relevant since many patients suffering from cancer diseases are often exposed to co-medications, food additives or herbal supplements able to activate PXR. A substantial part of the variability observed among patients might be caused by such interactions.
    Keywords
    Cancer Cell Biology; Cancer and Related Disorders

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