Abstract
A defining hallmark of primary and metastatic cancers is the migration and invasion of malignant cells. These invasive properties involve altered dynamics of the cytoskeleton and one of its major structural components β-actin. Here we identify AIM1 (absent in melanoma 1) as an actin-binding protein that suppresses pro-invasive properties in benign prostate epithelium. Depletion of AIM1 in prostate epithelial cells increases cytoskeletal remodeling, intracellular traction forces, cell migration and invasion, and anchorage-independent growth. In addition, decreased AIM1 expression results in increased metastatic dissemination in vivo. AIM1 strongly associates with the actin cytoskeleton in prostate epithelial cells in normal tissues, but not in prostate cancers. In addition to a mislocalization of AIM1 from the actin cytoskeleton in invasive cancers, advanced prostate cancers often harbor AIM1 deletion and reduced expression. These findings implicate AIM1 as a key suppressor of invasive phenotypes that becomes dysregulated in primary and metastatic prostate cancer.
Highlights
A defining hallmark of primary and metastatic cancers is the migration and invasion of malignant cells
Cancer cells must acquire the ability to invade through normal architectural confines in order to establish invasive carcinoma, local extension, and distant metastases
The ability to dynamically remodel the actin cytoskeleton is a key factor in such cancer cell invasion and understanding the molecular players involved in such processes is of critical importance[1,2,3, 48, 49]
Summary
A defining hallmark of primary and metastatic cancers is the migration and invasion of malignant cells These invasive properties involve altered dynamics of the cytoskeleton and one of its major structural components β-actin. Recent in silico meta-analyses of largescale expression data sets from normal prostate and prostate cancer demonstrate that genes involved in actin cytoskeleton regulation are differentially expressed between tumor and normal tissue in prostate cancer[8,9,10] Taken together, these findings strongly suggest that the actin cytoskeleton is profoundly dysregulated in prostate cancer. In vivo models further showed that loss of AIM1 led to increased micrometastases of prostate cancer xenografts These findings suggest that AIM1 is an important regulator of actin cytoskeletal dynamics, cell migration and invasion, and metastatic dissemination in prostate cancer
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