Pregnane X receptor suppresses proliferation and tumourigenicity of colon cancer cells.
BACKGROUND
Pregnane X receptor (PXR) is a nuclear receptor that regulates the metabolism and disposition of various xenobiotics and endobioitics. We investigated a novel PXR function in regulating colon tumourigenesis in this study.


METHODS
Histochemistry, transfection, cell proliferation assay, anchorage-alpha-dependent assay, xenograft, immunohistochemistry, immunofluorescence flow cytometry.


RESULTS
Using histochemistry analysis, we found that PXR expressions were lost or greatly diminished in many colon tumours. Ectopic expression of human PXR through stable transfection of PXR into colon cancer cell line HT29 significantly inhibited cell proliferation as determined by cell proliferation assay and anchorage-independent assay. Pregnane X receptor suppressed significantly HT29 xenograft tumour growth in nude mice compared with control (310+/-6.2 vs 120+/-6 mg, P<0.01). Immunohistochemistry and immunofluorescence analysis of Ki-67 on excised xenograft tumour tissues showed that PXR inhibited cancer cell proliferation. Furthermore, expressions of PXR and Ki-67 were mutually exclusive. The flow cytometry analysis indicated that PXR caused G(0)/G(1) cell-cycle arrest. p21(WAF1/CIP1) expression was markedly elevated whereas E2F1 expression was inhibited by PXR.


CONCLUSIONS
PXR inhibits the proliferation and tumourigenicity of colon cancer cells by controlling cell cycle at G(0)/G(1) cell phase by regulating p21(WAF1/CIP1) and E2F/Rb pathways.
Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, USA.
N
N
Ouyang
S
S
Ke
N
N
Eagleton
Y
Y
Xie
G
G
Chen
B
B
Laffins
H
H
Yao
B
B
Zhou
Y
Y
Tian
D000818:Animals; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000378:metabolism; D019073:HT29 Cells; D056945:Hep G2 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D025521:Tumor Suppressor Proteins