Abstract 315: Proteomic profiling of PTEN-deletion mouse prostate and its molecular pharmacodynamic responses to methylseleninic acid .

Abstract

Abstract Recent genomic and exome sequencing analyses revealed that loss of one allele of tumor suppressor gene Pten (phosphatase and tensin homolog deleted on chromosome 10) occurs frequently in primary prostate tumors, and homozygous deletion of Pten plays a casual role in advanced prostate cancer. Therefore, the prostate-specific PTEN-deletion driven prostate cancer mouse model resembles many features of human prostate cancer including disease progression to metastasis. Due to its high clinical relevance, this model is gaining wider utility for prostate cancer chemoprevention and therapeutic studies. Very recently, our collaborative team found that oral administration of methylseleninic acid (MSeA), a second-generation selenium compound, significantly inhibited PTEN-loss driven prostate tumorigenesis in vivo. In particular, the efficacy was associated with a super-activation of p53-p21 senescence pathway (PTEN-loss induced cellular senescence, PICS). To gain insights into additional molecular targets, we profiled the prostate proteome of PTEN-deletion mice. Whole prostates from PTEN-deletion mice (12-15 weeks of age) and their wild type littermate were obtained from the NCI Mouse Model Repository. Homogenate from 4 prostate pairs (Pten−/− and wild type) was prepared and digested individually and the peptides were labeled with 8-plex iTRAQTM reagents. Labeled peptides were pooled and analyzed by 2D-LC-MS/MS (LTQ Orbitrap Velos, Thermo Scientific). Out of 949 proteins identified, we further analyzed 152, the expressions of which were significantly and concordantly changed in all four pairs of mice. Among them, we detected enrichment of proteins related to cellular senescence (chitinase-3 like protein3 [CH3L3], cathelin-related antimicrobial peptide [Camp]), p53 (S100-A8, sorbitol dehydrogenase [DHSO]) and molecular targets involved in AKT signaling pathway (lipocalin 2, CH3L3), in line with the well-described AKT driven p53-mediated senescence in Pten-deficient prostate cancer mouse model. We also found decreased protein expression of GRP78 (78 kDa glucose-regulated protein), endoplasmin, probasin and TGM4 (transglutaminase4), same as we reported in the TRAMP model. Some of these protein changes (over or under) were predicated by published changes of their mRNA levels in prostates (probasin, TGM4, etc) and/or protein levels in sera (probasin, endoplasmin, GRP78, etc). Moreover, the congruence on some proteins (DHSO, S100-A8, etc) between the mouse model and clinical specimens (e.g. by C. Sawyers) highlights the clinical relevance of the model. The proteomic changes induced by MSeA are being investigated. Citation Format: Jinhui Zhang, Yibin Deng, Junxuan Lü. Proteomic profiling of PTEN-deletion mouse prostate and its molecular pharmacodynamic responses to methylseleninic acid . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 315. doi:10.1158/1538-7445.AM2013-315