The activity status of cofilin is directly related to invasion, intravasation, and metastasis of mammary tumors

Abstract

nderstanding the mechanisms controlling cancer cell invasion and metastasis constitutes a fundamental step in setting new strategies for diagnosis, prognosis, and therapy of metastatic cancers. LIM kinase1 (LIMK1) is a member of a novel class of serine-threonine protein kinases. Cofi lin, a LIMK1 substrate, is essential for the regulation of actin polymerization and depolymerization during cell migration. Previous studies have made opposite conclusions as to the role of LIMK1 in tumor cell motility and metastasis, claiming either an increase or decrease in cell motility and metastasis as a result of LIMK1 over expression (. We resolve this paradox by showing that the effects of LIMK1 expression on migration, intravasation, and metastasis of cancer cells can be most simply explained by its regulation of the output of the cofi lin pathway. LIMK1-mediated decreases or increases in the activity of the cofi lin pathway are shown to cause proportional decreases or increases in motility, intravasation, and metastasis of tumor cells.

The cofilin pathway in breast cancer invasion and metastasis

“…3), it was found to be significantly increased compared with non-invasive tumour cells from the same tumour with normal levels of LIMK1 and cofilin expression 43 . Furthermore, increasing the expression of LIMK1 alone in these mammary tumour cells inhibited the cofilin pathway and inhibited invasion and metastasis 43 . In mice with polyoma middle T oncogene (PyMT)-derived mammary tumours, invasive cells have increased expression of both LIMK1 and SSH, but not cofilin.…”

“…Unicellular organisms such as yeasts usually have only one ADF/cofilin-type protein, whereas multicellular organisms typically have several isoforms. In some cultured mammalian cell lines 40 and invasive mammary tumour cells 10,43 , cofilin 1 is the most abundant isoform, whereas ADF is expressed at much lower levels (5%). Therefore, for this Review 'cofilin' will refer to cofilin 1, the most abundant isoform found in invasive mammary tumour cells 10,12 .…”

“…3). This early transient of barbed ends is the output of the cofilin pathway 29 and this output is positively correlated with the invasive and metastatic activity of mammary tumour cells in vivo 12,43 .…”

“…3). This early transient of barbed ends is the output of the cofilin pathway 29 and this output is positively correlated with the invasive and metastatic activity of mammary tumour cells in vivo 12,43 .The transient cofilin activity occurs as a result of the near simultaneous activation, by the EGF receptor (EGFR), of the molecules within the cofilin pathway that both activate cofilin (PLCγ, SSH and chronophin) and inhibit cofilin (LIMK) (FIGS 1,2). In mammary tumour cells the activation and inhibition of cofilin must be balanced for transient cofilin activity to occur, be spatially localized 30 and for protrusion to occur optimally 29,30 .…”

“…In these experiments the expression of genes in the invasive subpopulation of tumour cells was compared to that in the average tumour cell isolated from the primary tumour. It was found that in rat mammary tumours derived from the orthotopic injection of mammary tumour cell lines, invasive tumour cells have increased transient expression of both cofilin and LIMK1 (REFS 10,43). Considering either cofilin or LIMK1 in isolation would have led to the paradoxical conclusion that LIMK1 overexpression, which leads to the inhibition of cofilin activity, is correlated with increased invasion at the same time as cofilin overexpression, which leads to an increase in cofilin activity, is also correlated with increased invasion.…”