The Cytoskeletal Protein Cyclase-Associated Protein 1 (CAP1) in Breast Cancer: Context-Dependent Roles in Both the Invasiveness and Proliferation of Cancer Cells and Underlying Cell Signals.

Guo-Lei Zhou,Rokib Hasan

doi:10.3390/ijms20112653

Guo-Lei Zhou, Rokib Hasan

Open Access

https://doi.org/10.3390/ijms20112653

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Abstract

As a conserved actin-regulating protein, CAP (adenylyl Cyclase-Associated Protein) functions to facilitate the rearrangement of the actin cytoskeleton. The ubiquitously expressed isoform CAP1 drives mammalian cell migration, and accordingly, most studies on the involvement of CAP1 in human cancers have largely been based on the rationale that up-regulated CAP1 will stimulate cancer cell migration and invasiveness. While findings from some studies reported so far support this case, lines of evidence largely from our recent studies point to a more complex and profound role for CAP1 in the invasiveness of cancer cells, where the potential activation of cell adhesion signaling is believed to play a key role. Moreover, CAP1 was also found to control proliferation in breast cancer cells, through the regulation of ERK (External signal-Regulated Kinase). Alterations in the activities of FAK (Focal Adhesion Kinase) and ERK from CAP1 depletion that are consistent to the opposite adhesion and proliferation phenotypes were detected in the metastatic and non-metastatic breast cancer cells. In this review, we begin with the overview of the literature on CAP, by highlighting the molecular functions of mammalian CAP1 in regulating the actin cytoskeleton and cell adhesion. We will next discuss the role of the FAK/ERK axis, and possibly Rap1, in mediating CAP1 signals to control breast cancer cell adhesion, invasiveness, and proliferation, largely based on our latest findings. Finally, we will discuss the relevance of these novel mechanistic insights to ultimately realizing the translational potential of CAP1 in targeted therapeutics for breast cancer.

Highlights

We previously reported that the mitochondrial shuttling of CAP1 was involved in the apoptosis of HeLa cells, through the intrinsic apoptotic pathway [66]; this function was largely attributed to the role of CAP1 as a component of the actin cytoskeleton
Studies from our group and others have solidly established roles for CAP1 in regulating cell functions, the de-regulation of which underlies the major hallmarks of cancer, such as the actin cytoskeleton, cell adhesion, migration, and proliferation [35,36,40]
Our studies unravel profound and complex roles for CAP1, involving key functions including adhesion, invasiveness, and proliferation in breast cancer cells. It remains to be better determined whether such roles of CAP1 are conserved across other cancer types. Regardless, these mechanistic insights help to shape a more complete and in-depth picture concerning the roles of CAP1 in human cancers, such insights are imperative before realizing that the translational potential of CAP1 can be possible

Summary

Introduction

Our follow-up study supports the conservation of this functional interaction between CAP1 and FAK in breast cancer cells, where CAP1 fulfills more complex roles in regulating FAK, and cell adhesion and invasiveness, depending on the cell type [40]. The fact that the depletion of CAP1 led to altered ERK activity suggests that CAP1 may play a role in the proliferation of breast cancer cells, which promoted us to test it. The signaling kinases FAK and ERK likely play central roles, by mediating CAP1 signals to control the key cancer cell functions, including adhesion, invasiveness, and proliferation.

Results

Conclusion