RAC1: an emerging therapeutic option for targeting cancer angiogenesis and metastasis

Abstract

Angiogenesis and metastasis are well recognized as processes fundamental to the development of malignancy. Both processes involve the coordination of multiple cellular and chemical activities through myriad signaling networks, providing a mass of potential targets for therapeutic intervention. This review will focus on one master regulator of cell motility, RAC1, and the existing data with regard to its role in cell motility, including particular roles for tumor angiogenesis and invasion/metastasis. We also emphasize the preclinical investigations carried out with RAC1 inhibitors to evaluate the therapeutic potential of this target. Herein, we explore potential future directions as well as the challenges of targeting RAC1 in the treatment of cancer. Recent insights at the molecular and cellular levels are paving the way for a more directed and detailed approach to target mechanisms of RAC1 regulating angiogenesis and metastasis. Understanding these mechanisms may provide insight into RAC1 signaling components as alternative therapeutic targets for tumor angiogenesis and metastasis.

Figure 1. RAC Pathways

Schematic illustration of RAC signaling pathways and effector functions. Emphasis is given to pathways known to affect tumor-related angiogenesis and metastasis.

Figure 2. Brefeldin A, a model for small-molecule inhibition of GTPases

a) Molecular structure of brefeldin A. b) and c) Crystal structure of brefeldin A (at center) in complex with its target GTPase (ARF, light blue) and GEF (Sec7, dark blue). Images are shown in both b) ribbon diagram and c) a space-filling model. The hydrolyzed GDP is seen at front with the catalytic magnesium ion in green. Brefeldin binds the surface of ARF that interacts with its GEFs and prevents the conformational changes that result in GDP for GTP exchange. Images were generated using Protein Data Bank (PDB) data published by Mossessova et al, manipulated with Jmol software, and rendered using POV-ray.

Figure 3. RAC inhibitors and RAC pathway inhibitors

Chemical structures for a) RAC inhibitors and b) inhibitors of RAC effector molecules discussed in the text.