Expanding the Roles for Pregnane X Receptor in Cancer: Proliferation and Drug Resistance in Ovarian Cancer

Purpose: We examined the presence of the pregnane X receptor (PXR) and its effects on ovarian cancer cells after activation by its cognate ligand. Experimental Design: SKOV-3 and OVCAR-8 ovarian carcinoma cells were analyzed for expression of PXR by quantitative reverse transcription-PCR and Western...

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Published in:Clinical cancer research 2008-09, Vol.14 (17), p.5332-5340
Main Authors: GUPTA, Divya, VENKATESH, Madhukumar, HONGWEI WANG, KIM, Sean, SINZ, Michael, GOLDBERG, Gary L, WHITNEY, Kathleen, LONGLEY, Clifford, MANI, Sridhar
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Biological and medical sciences
Cell Line, Tumor
Cell Proliferation
Drug Resistance, Multiple - genetics
Drug Resistance, Neoplasm - genetics
Female
Female genital diseases
Gynecology. Andrology. Obstetrics
Humans
Ligands
Medical sciences
metabolism
Mice
Mice, Inbred NOD
nuclear receptor
ovarian cancer
Ovarian Neoplasms - genetics
Pharmacology. Drug treatments
PXR
Receptors, Steroid - genetics
Transcriptional Activation
Tumors
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Summary:Purpose: We examined the presence of the pregnane X receptor (PXR) and its effects on ovarian cancer cells after activation by its cognate ligand. Experimental Design: SKOV-3 and OVCAR-8 ovarian carcinoma cells were analyzed for expression of PXR by quantitative reverse transcription-PCR and Western blot. Human ovarian cancer tissue was also analyzed for PXR expression by immunochemistry. Ligand (agonist)–induced PXR target genes were analyzed in SKOV-3 cells by quantitative reverse transcription-PCR. SKOV-3 cell proliferation was assessed by MTT assay. In vivo confirmation of in vitro effects of PXR ligands were done in NOD.SCID mice carrying SKOV-3 xenografts. Results: PXR is expressed in ovarian cancer cells. In SKOV-3 cells, PXR is functional and its activation by cognate ligands induces PXR target genes (CYP2B6, CYP3A4, and UGT1A1) but not MDR1 and MRP2. PXR activation in SKOV-3 cells induces cell proliferation and drug resistance. In mice harboring SKOV-3 xenografts, rifampicin (PXR agonist) induces cell proliferation and tumor growth. Conclusion: PXR activation, regardless of the type of ligand agonist present, promotes the “malignant” phenotype of cancer cells. These data serve as the basis for finding novel nontoxic inhibitors of PXR activation as a method to control cell growth and prevent induction of drug resistance.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-08-1033