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

Cancers

Vita M. Golubovskaya²  Baotran Ho²  Jeffrey Conroy¹  Song Liu³  Dan Wang³ 

[1]Genomics Shared Resource, Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA

[2] E-Mail:

[3]Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA

[4] E-Mails:

[5]Bioinformatics Core Facility, Biostatistics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA

[6] E-Mails:

关键词: Focal Adhesion Kinase;    p53;    Mdm-2;    Nutlin;    gene expression profiling;    microarrays;    combination therapy;   

DOI  :  10.3390/cancers6010166

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2014 by the authors; licensee MDPI, Basel, Switzerland.