Abstract LB-147: PXR inhibits PC3 tumor growth through regulation of HIF-1 expression
Authors: Jiuhui Wang, Yakun Chen, Daotai Nie
Journal: Cancer Research (2012)

Abstract Pregnane X receptor (PXR), a member of nuclear receptor family, regulates the metabolism and disposition of various xenobiotics and endobiotics in a ligand-dependent manner. Previous studies found that PXR is expressed in prostate and breast cancer cells and further it modulates tumor cell responses toward chemotherapy. Herein data are presented to suggest a role of PXR in regulating tumor growth via modulating the expression of HIF-1. To determine whether PXR regulates tumor growth, we generated PC3 cells with stable expression of human PXR (PC3-PXR) or constitutively active VP-PXR (PC3-VP-PXR). The effect of PXR on prostate tumor cell growth was investigated by MTS assay, cell number count and colony formation assay. The OD value and colony number of PC3-PXR and PC3-VP-PXR was significantly lower than that of PC3-pBabe, the vector control cells. The cell number of PC3-VP-PXR but not PC3-PXR was significant lower than that of vector control at day 3-6 after seeding. We also found that rifampicin, a well known agonist of human PXR, inhibited the proliferation of PC3-PXR at much lower concentrations (1-10 μM) than it did in the vector control cells. After implantation to nude athymic nu/nu mice subcutaneously, it was found the growth rate of tumor xenografts of PC3-PXR and PC3-VP-PXR was significantly inhibited when compared to the vector control group. The final average weight of the control group was 2.71 grams which was much larger than those from PC3-PXR and PC3-VP-PXR groups (0.25 and 0.53 gram, respectively). The data suggest an inhibitory effect of PXR on PC3 cell proliferation and tumor growth. Hypoxia-inducible factor-1 (HIF-1) is overexpressed in various human cancers and related to poor prognosis. We found that under normoxia, the expression of HIF-1α and HIF-2α was decreased in PC3 cell line transfected with PXR or VP-PXR. We also found that expression of VEGFA, C-met, EPO, IGF2 and key enzymes of glycolysis were also decreased in PC3-PXR and PC3-VP-PXR, indicating that the inhibitory effects of PXR on PC3 cell is related to the decreases in the expression of HIF-1α and HIF-2α, and their target genes. Interestingly, cobalt chloride (CoCl2), a hypoxia mimicking agent, inhibited the growth of PC3-PXR and PC3-VP-PXR cells much more profoundly than in PC3-pBabe cells. Though stabilizing HIF-1α, CoCl2 could induce expression of BNIP3 and NIX, which contribute to hypoxia-induced cell death. The induction rate of BNIP3 and NIX in PC3-VP-PXR was much higher than that in PC3-pBabe. Consistent with this, HIF-1α mRNA was increased after treatment with CoCl2 in PC3-VP-PXR but not in PC3-pBabe cells. The data suggest that PXR can sensitize tumor cells toward hypoxic stresses through increased expression of BNIP3 and NIX. In summary, our data suggested that in addition to its modulatory effects on tumor responses to chemotherapy, active PXR inhibits tumor cell proliferation in vitro and prostate tumor growth in vivo. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-147. doi:1538-7445.AM2012-LB-147