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In Vivo Quantitative Phosphoproteomic Profiling Identifies Novel Regulators Of Castration Resistant Prostate Cancer Growth

3647 words - 15 pages

LNCaP xenografts mimic many of the features of human prostate tumors making them a valuable model to study the mechanism of progression to CRPCa (12, 18). In order to obtain an overview of these mechanisms LNCaP xenografts were grown orthotopically in intact and castrated mice. The analysis of tumor growth show that castration resistant LNCaP tumors (CR-LNCaP) proliferate at a higher rate than androgen sensitive tumors (HS-LNCaP) at the time of harvest, 60 days after surgical orthotopic implantation (Figure 1A, B). This mimics the situation with human CRPCa, which proliferate at a higher rate than castration naïve localized tumors. Moreover, immunohistochemical analysis of orthotopically grown tumors show an increased number of Ki67 positive cells confirming an enhanced proliferative rate. Measurements of active caspase 3 by IHC show diminished activity in castration resistant tumors; indicating that both enhanced proliferation and diminished apoptosis contribute to the increased growth rate of tumors in castrated mice (Figure 1C and 1D). Next, we perform a comprehensive quantitative phosphoproteomic profiling using SILAC labeled LNCaP cells as internal, spiked-in controls in all samples analyzed (19) . In order to account for biological variation, 4 individual tumors were analyzed for each experimental group. In parallel, we also performed a genome-wide transcriptomic analysis (Figure 1E).
A total of 2782 phosphorylated peptides from a total of 1212 proteins were quantified in at least one of the samples. Sufficient data across biological replicates were obtained for 800 of those phosphopeptides. Statistical analysis identified differential expression for 98 peptides defined as fold changes of more than 50%, p<0.05 (Supplemental Table S1). Of these, 44 phosphopeptides showed increased levels (Table 1), while 54 exhibited decreased levels in castrated tumors as compared to those grown in intact mice (Supplemental Table S1). Gene ontology analysis indicates that proteins involved in cytoskeletal organization, regulation of cell morphogenesis and intracellular transport are enriched among proteins with increased phosphorylation (Supplemental Table S2). Phosphorylation of ACC1, the rate limiting enzyme in fatty acid synthesis (20) was the most prominent effect observed followed by changes in tyrosine kinase Lyn-Ser13 phosphorylation. We also identified elevated phosphorylation levels of cytoskeleton regulators: MAP1B, MAP4 and Stathmin, as well as signaling molecules MEK (p=0.06) and PRSA40 in CR-LNCaP. The later proteins are key members of the MAPK and mTORC1 signaling pathway suggesting that these pathways are involved in CR-LNCaP growth (36-37). Interestingly, we also identified increased phosphorylation of YAP1, a transcriptional co-activator that plays a key role in the mammalian hippo signaling pathway (38) and of PAK2 a regulator of cell motility that mediate the actions of Cdc42 and Rac small GTPases (21). Among proteins with...

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