Abstract 2587: Proteomic and transcriptomic profiling of effects of <i>Angelica gigas</i> ethanol extract on prostate neuroendocrine carcinomas of TRAMP mice
Authors: Jinhui Zhang, Li Li, Yong Zhang, Lei Wang, Cheng Jiang, Sung-Hoon kim, Junxuan Lu
Journal: Cancer Research (2012)

Abstract Angelica gigas Nakai (AGN) ethanol extract and its major component decursin have been reported to exert anti-cancer activities. Recently, our team reported that AGN was able to significantly suppress prostate neuroendocrine (NE) carcinogenesis in the TRAMP mice (Proc AACR, 2011, #5581). To gain insights into the in vivo mechanism(s) and potential targets, we used a systems-biology approach with a combination of proteomics and transcriptomics to analyze banked NE carcinoma tissues from vehicle- and AGN-treated groups (from 8 to 24 weeks of age). Global profiling of the proteome was performed by LC-MS/MS with iTRAQ labeling whereas the transcriptome was profiled by Illumina Mouse WG-6 BeadChip whole genome expression array. Angiogenesis Antibody Arrays (RayBiotech) were used to analyze angiogenesis-related proteins as a focused approach. Differentially expressed mRNA and proteins were subjected to bioinformatics analysis with Ingenuity Pathway Analysis (IPA). Antibody array analyses revealed that FGF2, a crucial stimulator of angiogenesis and promoter of tumor growth, was substantially decreased by AGN treatment. Other FGF family member such as FGF10, an oncogenic protein expressed in stromal cells, was also decreased by AGN at the mRNA level by more than 50%. In addition, mining of the microarray and proteomics data indicated that the changes of genes upstream and downstream of FGF2 were functionally consistent with AGN inhibiting FGF2/FGFR1 signaling at different levels of the transduction cascade. For example, FGFR1 mRNA level was decreased by AGN; FGFBP3, a binding protein which can protect FGFs from degradation, was decreased at the mRNA level; Dipeptidyl peptidase IV, which can block FGF2 signaling pathway in prostate cancer cells, was increased by AGN; “Good” stromal markers Myh11 and Myh4 which could be suppressed in FGF2 signaling pathway through Ras and ERK were substantially increased by AGN at both mRNA and protein levels. Some changes in mRNA levels suggested an anti-invasion potential of AGN. For example, the mRNA levels for urokinase plasminogen activator, Col1a1, Col1a2, MMP2, MMP3 and MMP12 were all decreased by AGN; Tropomyosin 2, reported to reduce the motility and invasion of cancer cells, was induced by AGN. Moreover, AGN up-regulated E-cadherin and down-regulated vimentin at both mRNA and protein levels, suggesting an anti-EMT action. IPA identified Akt, PI3K, p38MAPK, and ERK1/2 as distinct inferred network nodes after analyzing all AGN-responding genes. Furthermore, a number of genes down-regulated during TRAMP carcinogenesis such as Msmb, Actc1, Csrp1 and GSTM1 were increased by AGN treatment at protein and/or mRNA levels. Given the anti-angiogenesis, anti-invasion and anti-EMT effects of AGN observed, its anti-cancer activities may in part be mediated by affecting the tumor micro-environment in addition to cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2587. doi:1538-7445.AM2012-2587