Abstract
S100P protein is a potent inducer of metastasis in a model system, and its presence in cancer cells of patients is strongly associated with their reduced survival times. A well-established Furth Wistar rat metastasis model system, methods for measuring cell migration, and specific inhibitors were used to study pathways of motility-driven metastasis. Cells expressing C-terminal mutant S100P proteins display markedly-reduced S100P-driven metastasis in vivo and cell migration in vitro. These cells fail to display the low focal adhesion numbers observed in cells expressing wild-type S100P, and the mutant S100P proteins exhibit reduced biochemical interaction with non-muscle myosin heavy chain isoform IIA in vitro. Extracellular inhibitors of the S100P-dependent plasminogen activation pathway reduce, but only in part, wild-type S100P-dependent cell migration; they are without effect on S100P-negative cells or cells expressing C-terminal mutant S100P proteins and have no effect on the numbers of focal adhesions. Recombinant wild-type S100P protein, added extracellularly to S100P-negative cells, stimulates cell migration, which is abolished by these inhibitors. The results identify at least two S100P-dependent pathways of migration, one cell surface and the other intracellularly-linked, and identify its C-terminal lysine as a target for inhibiting multiple migration-promoting activities of S100P protein and S100P-driven metastasis.
Highlights
IntroductionPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations
Genes and proteins, including S100P, which confer a metastatic phenotype upon the benign Rama 37 cells in this system, have subsequently been shown to be associated with reduced patient survival time when they are found in the cancer cells of human patients [3,35,36,37]
Mutant S100P protein showed 2.1- and 1.8-fold higher numbers of vinculin and paxillin focal adhesions per cell, respectively, than wild-type S100P cells but 48% and 53% of those in the S100P-negative, control cells (Table 2; vinculin and paxillin, both p < 0.0001). ∆K95-mutant S100P protein exhibited mean numbers of vinculin and paxillin clusters per cell (Table 2) 5.1- and 4.5-fold higher, respectively, than cells expressing wild-type protein but, surprisingly, 1.2- and 1.3-fold higher than the control cells. These results suggest that mutation/deletion of the C-terminal lysine reduces the ability of S100P to alter the cytoskeletal organisation, a possible consequence of the reduced interaction of S100P with
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Elevated levels of some EF-hand-containing, calcium-binding members of the S100 family of proteins are associated with the development of many human cancers [1,2]. Increased immunohistochemical levels of S100P are associated with markedly reduced survival times of patients with breast [3,4], hepatocellular [5], early stage non-small cell lung [6], colon [7,8], and ovarian [9,10] cancers. The associations of S100P with reduced patient survival times are likely to arise from the ability of S100P to induce a metastatic phenotype [3]. The molecular pathways by which S100P exerts its metastasisinducing potential are not yet fully understood [2]
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