Nestin regulates prostate cancer cell invasion by influencing FAK and integrin localisation and functions

Abstract

BSTRACTNestin, an intermediate filament protein and marker of undifferentiated cells, is expressed in several cancers. Nestin is important for neuronal survival and is a regulator of myogenesis but its function in malignancy is ambiguous. We show that nestin downregulation leads to a redistribution of phosphorylated focal adhesion kinase (pFAK, also known as PTK2) to focal adhesions and alterations in focal adhesion turnover. Nestin downregulation also leads to an increase in the protein levels of integrin a5b1 at the cell membrane, activation of integrin b1 and an increase in integrin clustering. These effects have striking consequences for cell invasion, as nestin downregulation leads to a significant increase in pFAK-and integrin-dependent matrix degradation and cell invasion. Our results indicate that nestin regulates the localisation and functions of FAK and integrin. Because nestin has been shown to be prevalent in a number of specific cancers, our observations have broad ramifications for the roles of nestin in malignant transformation.

Differential DNA methylation profile of key genes in malignant prostate epithelial cells transformed by inorganic arsenic or cadmium

“…However other controlling factors may also be at play, since in a mouse neuronal cell line histone acetylation, rather than DNA methylation, is required to regulate NES expression (Han et al , 2009). Whereas initial reports indicated that NES is involved in prostate cancer cell migration, invasion, and metastasis (Kleeberger et al , 2007), more recent work demonstrates an inhibitory role for NES in prostate cancer cell migration and invasion (Hyder et al , 2014). In the work by Hyder et al, (2014), decreased NES expression regulates phosphorylated focal adhesion kinase activity, integrin localization on the cell membrane, and extracellular matrix proteolysis resulting in larger cells that spread out upon the tissue culture growth surface and have increased invasive properties.…”

“…Whereas initial reports indicated that NES is involved in prostate cancer cell migration, invasion, and metastasis (Kleeberger et al , 2007), more recent work demonstrates an inhibitory role for NES in prostate cancer cell migration and invasion (Hyder et al , 2014). In the work by Hyder et al, (2014), decreased NES expression regulates phosphorylated focal adhesion kinase activity, integrin localization on the cell membrane, and extracellular matrix proteolysis resulting in larger cells that spread out upon the tissue culture growth surface and have increased invasive properties. Interestingly, the iAs transformed cells in our study often show a similar phenotype, with increased size, more extensive spreading, and increased invasion.…”

Intermediate filaments in cell migration and invasion: the unusual suspects

“…For instance, synemin contributes to the migratory properties of astrocytoma by influencing focal adhesions through its specific interaction with zyxin [68] and also by controling actin dynamics [69]. Nestin is a specific regulator of FAK phosphorylation and VASP dynamics and thereby controls the invasive capacity of prostate cancer cells [70]. Keratins 6a and 6b (K6), the expression of which is rapidly induced in wound-proximal epidermal keratinocytes, directly interact with Src to prevent its activation during cell migration.…”

Reconsideration of the clinical and histopathological significance of angiogenesis in prostate cancer: Usefulness and limitations of microvessel density measurement

“…These pathological roles of nestin are supported by a similar study by other investigators. 57 In contrast, nestin is recognized as a cancer stem cell marker of prostate cancer, and there are several reports on nestin as a cancer stem cell. 58,59 However, unfortunately, there is no report regarding MVD measured by using anti-nestin antibody.…”