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Abstract
HER-2 is constitutively activated and overexpressed in many cancers, and its inhibition in colon cancer cells diminishes tumorigenicity and induces apoptosis. Little is known about the regulation of HER-2 signaling in colon cancer cells. Integrin α5/β1 expression is frequently lost in colorectal cancer cells compared with normal intestinal epithelium, and colon cancer cells lacking integrin α5/β1 expression utilize HER-2 signaling for proliferation and tumorigenicity. Re-expression of integrin α5/β1 in colon cancer cells abrogated their tumorigenicity, but how this occurs is not well known. Stable expression of integrin α5/β1 in colon cancer cells with little or no detectable integrin α5/β1 protein expression resulted in the post-transcriptional down-regulation of HER-2 protein. Integrin α5/β1 was found to interact with HER-2, and the cytoplasmic domain of integrin α5/β1 was sufficient to mediate HER-2 down-regulation. Integrin α5/β1-mediated down-regulation of HER-2 was the result of increased lysosomal targeting. The inhibition of HER-2 signaling represents a potential mechanism by which integrin α5/β1 exerts its tumor suppressor-like activity in colon cancer cells. These results also suggest that a novel function for integrin α5/β1 is the control of HER-2 expression.
Highlights
Ing tumor angiogenesis and survival [6, 7]
Because HER-2 is commonly overexpressed in colorectal cancers, we examined whether a relationship between integrin ␣5/1 and HER-2 expression existed
Another study recently showed that increased signaling through integrin ␣6/1 resulted in ectodomain cleavage of HER-2 [20]
Summary
The inhibition of HER-2 signaling represents a potential mechanism by which integrin ␣5/1 exerts its tumor suppressor-like activity in colon cancer cells These results suggest that a novel function for integrin ␣5/1 is the control of HER-2 expression. Stable expression of integrin ␣5/1 in a colon cancer cell line resulted in a significant decrease in amphiregulin mRNA levels and the loss of constitutive EGFR autophosphorylation, which was seen in the control cells. These results suggest that the loss of integrin ␣5/1 expression in colon cells may lead to constitutive activation of EGFR and HER-2-mediated signaling, which in turn promotes growth factor and extracellular matrix independence
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