title: Proteomics analyses of prostate cancer cells reveal cellular pathways associated with androgen resistance.
abstract: While significant advances have been made in the diagnosis and treatment of prostate cancer, each year tens of thousands of men still die from prostate cancer in the United States. Thus, greater understanding of cellular pathways and molecular basis of prostate cancer progression in the development of androgen resistance is needed to treat these lethal phenotypes. To dissect the mechanism of androgen resistance, we utilize a proteomics approach to study the development of androgen resistance in LNCaP prostate cancer cells. Our results showed the predominant involvement of metabolic pathways that were elevated in androgen resistance phenotype. We further found the amplification of PI3K/AKT pathway and the overexpression of proteasome proteins while the mitochondrial oxidation phosphorylation was severely hampered in castration-resistant LNCaP-95 cells compared to LNCaP cells. Interestingly, we also found the induction of Dicer, a cytoplasmic endoribonuclease microRNA regulator in the androgen-ablated LNCaP-95 prostate cancer cells. We verified some of these data by orthogonal methods including Western blot analysis and in castrated animal xenograft studies. To our knowledge, this is the first report showing induced expression of proteasome proteins in androgen ablation prostate cancer cells. If validated in clinical studies, the findings will have significant implications in understanding the complexity of biochemical recurrence in prostate cancer.
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Naseruddin
authors.initials: N
authors.lastname: Höti
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Punit
authors.initials: P
authors.lastname: Shah
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Yingwei
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Shuang
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000728:Androgens / Q000494:pharmacology*; D045744:Cell Line, Tumor; D048430:Cell Shape / Q000187:drug effects; D002853:Chromatography, Liquid; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D008297:Male; D010085:Oxidative Phosphorylation / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D040901:Proteomics / Q000379:methods*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D053719:Tandem Mass Spectrometry; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000728:Androgens; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D046988:Proteasome Endopeptidase Complex
keywords: Androgen resistance; LC-MS/MS; Oxidative phosphorylation; PI3K/AKT; Proteasome