Gene Expression Profiling Identifies Important Genes Affected by R2 Compound Disrupting FAK and P53 Complex.
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.
Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA. Vita.Golubovskaya@roswellpark.org.
Vita M
VM
Golubovskaya
Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA. Baotran.Ho@roswellpark.org.
Baotran
B
Ho
Genomics Shared Resource, Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA. Jeffrey.Conroy@Roswellpark.org.
Jeffrey
J
Conroy
Department of Biostatistics & Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA. Song.Liu@roswellpark.org.
Song
S
Liu
Department of Biostatistics & Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA. Dan.Wang@roswellpark.org.
Dan
D
Wang
Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA. William.Cance@roswellpark.org.
William G
WG
Cance