Abstract
The actin-regulating protein CAP1 is implicated in the invasiveness of human cancers. However, the exact role remains elusive and controversial given lines of conflicting evidence. Moreover, a potential role in the proliferative transformation has largely been overlooked. Further establishing the role and dissecting underlying mechanisms are imperative before targeting CAP1 can become a possibility for cancer treatment. Here we report our findings that CAP1 exerts cell type-dependent functions in the invasiveness of breast cancer cells. Depletion of CAP1 in the metastatic MDA-MB-231 and BT-549 cancer cells stimulated the metastatic potential while it actually inhibited it in the non-metastatic MCF-7 cancer cells or in normal cells. Moreover, we demonstrate functions for CAP1 in cancer cell proliferation and anchorage-independent growth, again in a cell context-dependent manner. Importantly, we identify pivotal roles for the ERK-centered signaling in mediating both CAP1 functions. Phosphor mutants of CAP1 at the S307/S309 regulatory site had compromised rescue effects for both the invasiveness and proliferation in CAP1-knockdown cells, suggesting that CAP1 likely mediates upstream cell signals to control both functions. These novel mechanistic insights may ultimately open up avenues for strategies targeting CAP1 in the treatment of breast cancer, tailored for specific types of the highly diverse disease.
Highlights
Dynamic rearrangement of the actin cytoskeleton provides essential driving force for directional cell movement
When we examined cell morphologies, we found that while both the AA and DD mutants partially rescued the cell morphology compared to WTCAP1 (R-Wild Type (WT)), suggesting that the mutants are partially functional in that regard, the mutant cells did not spread as well as the cells re-expressing WTCAP1 in overnight culture (Fig. S4A)
While majority of the evidence to date suggests a stimulatory role, conflicting evidence exists against up-regulation of CAP1 in human cancers and a universal role in promoting cancer invasiveness
Summary
Dynamic rearrangement of the actin cytoskeleton provides essential driving force for directional cell movement. Mammals have two CAP isoforms, CAP1 and CAP2, and CAP1 is ubiquitously expressed[3,4] Recent studies, including those from our group, have established roles for mammalian CAP1 in regulating the actin cytoskeleton and cell migration[5,6,7]. Depletion of CAP1 in HeLa cells stimulated migration and invasion substantially[6], where activation of cell adhesion signaling apparently played a key role and overcame the negative effect from the reduced actin dynamics. The studies unravel novel cell type-specific functions for CAP1, and the role in proliferative transformation that has largely been overlooked, along with underlying mechanisms These mechanistic insights carry important implications in developing strategies targeting CAP1 in the treatment of breast cancer, which is a highly diverse disease
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