Expanding the roles for pregnane X receptor in cancer: proliferation and drug resistance in ovarian cancer.
OBJECTIVE
We examined the presence of the pregnane X receptor (PXR) and its effects on ovarian cancer cells after activation by its cognate ligand.


METHODS
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.


CONCLUSIONS
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.
Gupta
Divya
D
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology and Women's Health, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY 10461, USA.
Venkatesh
Madhukumar
M
Wang
Hongwei
H
Kim
Sean
S
Sinz
Michael
M
Goldberg
Gary L
GL
Whitney
Kathleen
K
Longley
Clifford
C
Mani
Sridhar
S