Vimentin in cancer and its potential as a molecular target for cancer therapy

Abstract

Vimentin, a major constituent of the intermediate filament family of proteins, is ubiquitously expressed in normal mesenchymal cells and is known to maintain cellular integrity and provide resistance against stress. Vimentin is overexpressed in various epithelial cancers, including prostate cancer, gastrointestinal tumors, tumors of the central nervous system, breast cancer, malignant melanoma, and lung cancer. Vimentin's overexpression in cancer correlates well with accelerated tumor growth, invasion, and poor prognosis; however, the role of vimentin in cancer progression remains obscure. In recent years, vimentin has been recognized as a marker for epithelial-mesenchymal transition (EMT). Although EMT is associated with several tumorigenic events, vimentin's role in the underlying events mediating these processes remains unknown. By virtue of its overexpression in cancer and its association with tumor growth and metastasis, vimentin serves as an attractive potential target for cancer therapy; however, more research would be crucial to evaluate its specific role in cancer. Our recent discovery of a vimentin-binding mini-peptide has generated further impetus for vimentin-targeted tumor-specific therapy. Furthermore, research directed toward elucidating the role of vimentin in various signaling pathways would reveal new approaches for the development of therapeutic agents. This review summarizes the expression and functions of vimentin in various types of cancer and suggests some directions toward future cancer therapy utilizing vimentin as a potential molecular target.

Figures

Figure 1. Vimentin's role in cell signaling

In cytosol, vimentin was shown to interact with phosphorylated-Erk and protect the phosphorylation by inhibiting phosphatases which allows it to travel long distances within the cell. Also, vimentin's interaction with 14-3-3 proteins prevents the formation of 14-3-3-Raf complex and thereby regulates several cell processes by depleting the availability of free 14-3-3. Further, AKT1 was shown to phosphorylate vimentin and protect it from caspase induced proteolysis; therefore the freely available vimentin is participating in processes that lead to increased migration and invasive capacity of the cells. In the nucleus, vimentin was shown to regulate p21 expression, while the complex formed between ATF4 and vimentin prevents the active transcription by ATF4. Extracellularly, vimentin specific receptors are not yet identified, however one of the possible receptors NKp46 was identified on natural killer cells to which vimentin acts as a specific ligand. Although reports indicate that vimentin is also secreted, neither its function nor the mechanism of secretion is clear.

Figure 2. Vimentin's role in cancer

Over-expression of vimentin is frequently associated with increased migration/invasion capacity of the cells. Vimentin is mainly used as a marker for EMT in association with other known markers. Majority of the cancers over express vimentin and it is used as an indicator of poor prognosis.