title: Metabolomic profiling identifies biochemical pathways associated with castration-resistant prostate cancer.
abstract: Despite recent developments in treatment strategies, castration-resistant prostate cancer (CRPC) is still the second leading cause of cancer-associated mortality among American men, the biological underpinnings of which are not well understood. To this end, we measured levels of 150 metabolites and examined the rate of utilization of 184 metabolites in metastatic androgen-dependent prostate cancer (AD) and CRPC cell lines using a combination of targeted mass spectrometry and metabolic phenotyping. Metabolic data were used to derive biochemical pathways that were enriched in CRPC, using Oncomine concept maps (OCM). The enriched pathways were then examined in-silico for their association with treatment failure (i.e., prostate specific antigen (PSA) recurrence or biochemical recurrence) using published clinically annotated gene expression data sets. Our results indicate that a total of 19 metabolites were altered in CRPC compared to AD cell lines. These altered metabolites mapped to a highly interconnected network of biochemical pathways that describe UDP glucuronosyltransferase (UGT) activity. We observed an association with time to treatment failure in an analysis employing genes restricted to this pathway in three independent gene expression data sets. In summary, our studies highlight the value of employing metabolomic strategies in cell lines to derive potentially clinically useful predictive tools.
authors.affiliation: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, ‡Alkek Center for Molecular Discovery, §Molecular and Cellular Biology, and ∥Department of Surgery, Baylor College of Medicine , Houston, Texas 77030, United States.
authors.forename: Akash K
authors.initials: AK
authors.lastname: Kaushik
authors.forename: Shaiju K
authors.initials: SK
authors.lastname: Vareed
authors.forename: Sumanta
authors.initials: S
authors.lastname: Basu
authors.forename: Vasanta
authors.initials: V
authors.lastname: Putluri
authors.forename: Nagireddy
authors.initials: N
authors.lastname: Putluri
authors.forename: Katrin
authors.initials: K
authors.lastname: Panzitt
authors.forename: Christine A
authors.initials: CA
authors.lastname: Brennan
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
authors.forename: Ismael A
authors.initials: IA
authors.lastname: Vergara
authors.forename: Nicholas
authors.initials: N
authors.lastname: Erho
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Weigel
authors.forename: Nicholas
authors.initials: N
authors.lastname: Mitsiades
authors.forename: Ali
authors.initials: A
authors.lastname: Shojaie
authors.forename: Ganesh
authors.initials: G
authors.lastname: Palapattu
authors.forename: George
authors.initials: G
authors.lastname: Michailidis
authors.forename: Arun
authors.initials: A
authors.lastname: Sreekumar
mesh_terms: D045744:Cell Line, Tumor; D002853:Chromatography, Liquid; D015870:Gene Expression; D014453:Glucuronosyltransferase / Q000378:metabolism; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D055432:Metabolomics; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*
chemical_list: D014453:Glucuronosyltransferase