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Abstract
We have previously described a novel modulator of the actin cytoskeleton that also regulates Ras and mitogen-activated protein kinase activities in TGFβ-sensitive epithelial cells. Here we examined the functional role of this signaling regulatory protein (km23-1) in mediating the migration, invasion, and tumor growth of human colorectal carcinoma (CRC) cells. We show that small interfering RNA (siRNA) depletion of km23-1 in human CRC cells inhibited constitutive extracellular signal-regulated kinase (ERK) activation, as well as pro-invasive ERK effector functions that include phosphorylation of Elk-1, constitutive regulation of c-Fos-DNA binding, TGFβ1 promoter transactivation, and TGFβ1 secretion. In addition, knockdown of km23-1 reduced the paracrine effects of CRC cell-secreted factors in conditioned medium and in fibroblast co-cultures. Moreover, km23-1 depletion in human CRC cells reduced cell migration and invasion, as well as expression of the ERK-regulated, metastasis-associated scaffold protein Ezrin. Finally, km23-1 inhibition significantly suppressed tumor formation in vivo. Thus, our results implicate km23-1 as a novel anti-metastasis target for human colon carcinoma cells, capable of decreasing tumor growth and invasion via a mechanism involving suppression of various pro-migratory features of CRC. These include a reduction in ERK signaling, diminished TGFβ1 production, decreased expression of the plasma membrane-cytoskeletal linker Ezrin, as well as attenuation of the paracrine effects of colon carcinoma-secreted factors on fibroblast migration and mitogenesis. As such, km23-1 inhibitors may represent a viable therapeutic strategy for interfering with colon cancer progression and invasion.
Highlights
Human colorectal cancer (CRC) is one of the most common malignancies, with distant metastases representing the greatest threat to patient survival [1]
In RKO cells stably transfected with km23-1 small interfering RNA (siRNA), the phosphorylation of ERK1/2 was significantly suppressed, whereas there was no effect on total ERK1/2 expression levels
Our results demonstrate that depletion of km23-1 expression inhibits extracellular signalregulated kinase (ERK) activation in three different cancer cell lines with constitutively activated ERK
Summary
Human colorectal cancer (CRC) is one of the most common malignancies, with distant metastases representing the greatest threat to patient survival [1]. Various cellular events are known to be associated with this increased potential for malignant cells to spread to local and distant sites. Among these events are elevated expression or activity of signaling components and cellular scaffolds [2,4]. Nearly 50% of colon cancers harbor activating mutations in KRAS and 5–18% display activating BRAF mutations [10,11]. These mutations in the K-Ras and B-Raf signaling intermediates occur in a mutually exclusive manner [10]
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