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

Authors' Affiliations: ¹ Division of Gynecologic Oncology, Department of Obstetrics and Gynecology and Women's Health, Albert Einstein College of Medicine and Montefiore Medical Center; ² Albert Einstein Cancer Center and ³ Department of Pathology, Albert Einstein College of Medicine, Bronx, New York; and ⁴ Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey; and ⁵ Enzon Pharmaceuticals, Inc., Piscataway, New Jersey

Requests for reprints: Sridhar Mani, Albert Einstein Cancer Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Chanin 302D-1, Bronx, NY 10461. Phone: 718-430-2871; Fax: 718-904-2830; E-mail: smani{at}montefiore.org.

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.