Gene Expression Profiling Identifies Important Genes Affected by R2 Compound Disrupting FAK and P53 Complex

Abstract

Focal Adhesion Kinase (FAK) is a non-receptor kinase that plays an important role in many cellular processes: adhesion, proliferation, invasion, angiogenesis, metastasis and survival. Recently, we have shown that Roslin 2 or R2 (1-benzyl-15,3,5,7-tetraazatricyclo[3.3.1.1~3,7~]decane) compound disrupts FAK and p53 proteins, activates p53 transcriptional activity, and blocks tumor growth. In this report we performed a microarray gene expression analysis of R2-treated HCT116 p53+/+ and p53−/− cells and detected 1484 genes that were significantly up- or down-regulated (p < 0.05) in HCT116 p53+/+ cells but not in p53−/− cells. Among up-regulated genes in HCT p53+/+ cells we detected critical p53 targets: Mdm-2, Noxa-1, and RIP1. Among down-regulated genes, Met, PLK2, KIF14, BIRC2 and other genes were identified. In addition, a combination of R2 compound with M13 compound that disrupts FAK and Mmd-2 complex or R2 and Nutlin-1 that disrupts Mdm-2 and p53 decreased clonogenicity of HCT116 p53+/+ colon cancer cells more significantly than each agent alone in a p53-dependent manner. Thus, the report detects gene expression profile in response to R2 treatment and demonstrates that the combination of drugs targeting FAK, Mdm-2, and p53 can be a novel therapy approach.

Targeting FAK scaffold functions inhibits human renal cell carcinoma growth

“…Recently, it was shown that interference with several FAK protein-protein interactions has a dramatic effect on cancer cell survival and progression. [49][50][51][52] During the course of our study, Megison et al 29 demonstrated that in vitro and in vivo abrogation of FAK impacted cancer cell survival and growth in pediatric kidney tumors. Here, we show that FAK is critically associated both in vitro and in vivo with human renal carcinogenesis in adults.…”

“…Although this pharmacological strategy is in its infancy, FAK scaffold interaction can be disrupted by peptides or small molecule inhibitors. Recently, it was shown that interference with several FAK protein‐protein interactions has a dramatic effect on cancer cell survival and progression …”

Focal adhesion kinase and p53 synergistically decrease neuroblastoma cell survival

“…They reported that co-infection of RPMI 2650 human squamous carcinoma cells with Ad-p53 in conjunction with Ad-FRNK, a dominant-negative FAK inhibitor, resulted in more cellular apoptosis than when this cell line was infected with either agent alone [48]. Recent gene expression profiling showed that disruption of FAK and p53 proteins leads to decreased clonogenicity of colon cancer p53+/+ cell line [49]. On a general level, investigators have suggested that proteins such as FAK may bind to p53, sequestering it in the cytoplasm of the cell, thus preventing it from entering the nucleus and functioning as a transcription factor for cell survival proteins [16].…”

Role of SH3PXD2B in Breast Cancer Lung Metastasis through Computational Structural and Systems Perspective

“…Based on scientific literature the proteins involved in breast cancer metastasis to lung and published data for their associated transcription factors available in multiple databases was collected to construct an integrated bio-molecular interaction network of Transcription Factor-Target Gene (TFTG). In our study, we used an enlisted 22 metastatic proteins reported through various literatures playing a crucial role in breast cancer lung metastasis [116][117][118][119][120][121][122][123][124][125][126]. The associated transcription factors regulating the expression of these metastatic proteins were fished from the TF2DNA and TF link databases, which offer detailed and extremely reliable information on transcription factor -target gene interactions for numerous organisms, including Homo sapiens.…”