Microfilament Actin Remodeling as a Potential Target for Cancer Drug Development

Abstract

Actin was first identified in non-muscle cells only about three decades ago, and at about the same time, it was found that actin filaments were disrupted in the malignant transformed cells. The actin network is a rather complex, yet important structural and functional system of all eukaryotic cells. Actin filaments provide the basic infrastructure for maintaining cell morphology and functions such as adhesion, motility, exocytosis, endocytosis, and cell division. Growing evidence from this laboratory and others shows that alterations of actin polymerization, or actin remodeling, plays a pivotal role in regulating the morphologic and phenotypic events of a malignant cell. Actin remodeling is the result of activation of oncogenic actin signaling pathways (e.g., Ras and Src), or inactivation of several important actin-binding proteins that have tumor suppressor functions (e.g., gelsolin). Distinctive protein expression patterns of some of these genes in cancer and progressive carcinogenic processes have been observed. It has become evident that actin dynamics are regulated by a complex interplay of the small GTPase proteins of Ras superfamily Rac, Rho, and Cdc42, and efforts to develop specific inhibitors for these small G proteins as anticancer drug are underway. In this review we will discuss how actin remodeling is altered in the malignant transformation process, the functional significance of actin alteration in association with malignant phenotypes, and the approaches of targeting actin remodeling for chemopreventive and chemotherapeutic drug development. Approaches including using nature products directly modulating actin polymerization, using inhibitors of actin pathway small G proteins, and using gene-augmentation for actin binding proteins will be discussed. In addition, the concept of using F/G-actin ratio as a surrogate marker for actin-pathway based therapy will also be introduced.

Mer receptor tyrosine kinase promotes invasion and survival in glioblastoma multiforme

“…41 Previous studies have demonstrated that cancer cells are able to invade in 3D after treatment with a matrix metalloproteinase inhibitor cocktail, whilst showing the typical features of amoeboid invasiveness during migration; this indicates that blocking extracellular matrix proteolysis promotes mesenchymal-amoeboid transitions. 36,42 Inhibition of the ATPase activity of actin and myosin could reduce cell motility, 43 but targeting such fundamental cytoskeleton components might have severe side effects. A further attractive therapeutic strategy for GBM treatment has been shown to target cell surface growth factor receptors such as epidermal growth factor receptor, platelet-derived growth factor receptor and vascular endothelial growth factor receptor.…”

Green tea induces annexin-I expression in human lung adenocarcinoma A549 cells: involvement of annexin-I in actin remodeling

“…34 At a later stage, the tumor cells may regain the actin polymerization capability through the activation of Ras superfamily GTPase (Rac/Rho/CDC42) that causes re-distribution of actin filaments in a way favoring cellular movement and migration. 14 Green tea stimulates annexin-1 expression Q-Y Lu et al has been shown that the distribution of actin filaments, rather than the net actin polymerization, may be more important in determining cellular adhesion and motility, at least in epithelial cells.…”

Actin: a novel interaction partner of WT1 influencing its cell dynamic properties

“…Alterations of actin polymerization drive invasive morphological changes in malignant cells including modulation of adhesion complexes and, associated with them, microfilaments (Gimona, 2008). Actin remodelling could be the result of activation of oncogenic signalling pathways, or misexpression of some actin-binding proteins (Rao and Li, 2004). Wt1 was named as one of the proteins implicated in actin cytoskeletal changes in cancer cells (Jomgeow et al, 2006) and cultured podocytes (Viney et al, 2007).…”