title: Identification of CAD as an androgen receptor interactant and an early marker of prostate tumor recurrence.
abstract: Markers of prostate tumor recurrence after radical prostatectomy are lacking and highly demanded. The androgen receptor (AR) is a nuclear receptor that plays a pivotal role in normal and cancerous prostate tissue. AR interacts with a number of proteins modulating its stability, localization, and activity. To test the hypothesis that an increased expression of AR partners might foster tumor development, we immunopurified AR partners in human tumors xenografted into mice. One of the identified AR partners was the multifunctional enzyme carbamoyl-phosphate synthetase II, aspartate transcarbamylase, and dihydroorotase (CAD), which catalyzes the 3 initial steps of pyrimidine biosynthesis. We combined experiments in C4-2, LNCaP, 22RV1, and PC3 human prostate cell lines and analysis of frozen radical prostatectomy samples to study the CAD-AR interaction. We show here that in prostate tumor cells, CAD fosters AR translocation into the nucleus and stimulates its transcriptional activity. Notably, in radical prostatectomy specimens, CAD expression was not correlated with proliferation markers, but a higher CAD mRNA level was associated with local tumor extension (P=0.049) and cancer relapse (P=0.017). These results demonstrate an unsuspected function for a key metabolic enzyme and identify CAD as a potential predictive marker of cancer relapse.
authors: Centre National de la Recherche Scientifique, University of Paris Sud,Villejuif, France.
authors: Aurélie
authors: A
authors: Morin
authors: Lauriane
authors: L
authors: Fritsch
authors: Jacques R R
authors: JR
authors: Mathieu
authors: Cristèle
authors: C
authors: Gilbert
authors: Basma
authors: B
authors: Guarmit
authors: Virginie
authors: V
authors: Firlej
authors: Catherine
authors: C
authors: Gallou-Kabani
authors: Annick
authors: A
authors: Vieillefond
authors: Nicolas Barry
authors: NB
authors: Delongchamps
authors: Florence
authors: F
authors: Cabon
mesh_terms: D000728:Androgens / Q000378:metabolism; D000818:Animals; D001221:Aspartate Carbamoyltransferase / Q000235:genetics / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing) / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004080:Dihydroorotase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis* / Q000378:metabolism; D009368:Neoplasm Transplantation; D011237:Predictive Value of Tests; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000378:metabolism; D011743:Pyrimidines / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000494:pharmacology; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology; D014183:Transplantation, Heterologous
chemical_list: D000728:Androgens; D014408:Biomarkers, Tumor; C033626:CAD trifunctional enzyme; D011743:Pyrimidines; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D001221:Aspartate Carbamoyltransferase; D004080:Dihydroorotase; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing); C030986:pyrimidine