Decreased tumor progression and invasion by a novel anti-cell motility target for human colorectal carcinoma cells

• Published in: PloS one 2013-06, Vol.8 (6), p.e66439-e66439
• Main Authors: Jin, Qunyan, Liu, Guangming, Domeier, Phillip P, Ding, Wei, Mulder, Kathleen M
• Format: Article
• Language: English
• Subjects: Actin; Animals; Biochemistry; Biology; c-Fos protein; Cancer metastasis; Care and treatment; Cell adhesion & migration; Cell Line, Tumor; Cell migration; Cell Movement; Collagen - chemistry; Colon; Colon cancer; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Conditioning; Cytoplasmic Dyneins - antagonists & inhibitors; Cytoplasmic Dyneins - genetics; Cytoplasmic Dyneins - metabolism; Cytoskeletal Proteins - antagonists & inhibitors; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; Cytoskeleton; Deoxyribonucleic acid; Depletion; Development and progression; Diffusion Chambers, Culture; DNA; Drug Combinations; Elk; Epithelial cells; ets-Domain Protein Elk-1 - genetics; ets-Domain Protein Elk-1 - metabolism; Extracellular signal-regulated kinase; Extracellular Signal-Regulated MAP Kinases - genetics; Extracellular Signal-Regulated MAP Kinases - metabolism; Ezrin; Female; Gene expression; Gene Expression Regulation, Neoplastic; Genetic aspects; Genetic Vectors; Genotype & phenotype; Growth factors; Health aspects; Humans; Invasiveness; Kinases; Laminin - chemistry; Lentivirus - genetics; MAP kinase; Medicine; Metastases; Metastasis; Mice; Mice, Nude; Mitogens; Molecular biology; Motility; Mutation; Neoplasm Invasiveness; Neoplasm Transplantation; Paracrine signalling; Phosphorylation; Physiological aspects; Protein kinase; Proteins; Proteoglycans - chemistry; Proto-Oncogene Proteins c-fos - genetics; Proto-Oncogene Proteins c-fos - metabolism; Ribonucleic acid; RNA; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Secretion; Signal Transduction; siRNA; Transcription factors; Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - metabolism; Transforming growth factor-b1; Tumor Burden - genetics; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0066439

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.