p38γ Promotes Breast Cancer Cell Motility and Metastasis through Regulation of RhoC GTPase, Cytoskeletal Architecture, and a Novel Leading Edge Behavior

Abstract

Understanding the molecular alterations that confer cancer cells with motile, metastatic properties is needed to improve patient survival. Here we report that p38γ MAPK regulates breast cancer cell motility and metastasis, in part by controlling expression of the metastasis-associated small GTPase RhoC. This p38γ-RhoC regulatory connection was mediated by a novel mechanism of modulating RhoC ubiquitination. This relationship persisted across multiple cell lines and in clinical breast cancer specimens. Using a computational mechanical model based on the finite element method, we demonstrated that p38γ-mediated cytoskeletal changes are sufficient to control cell motility. This model predicted novel dynamics of leading edge actin protrusions, which were experimentally verified and established to be closely related to cell shape and cytoskeletal morphology. Clinical relevance was supported by evidence that elevated expression of p38γ associated with lower overall survival of breast cancer patients. Taken together, our results offer a detailed characterization of how p38γ contributes to breast cancer progression, presents a new mechanics-based analysis of cell motility, and discovers a leading edge behavior in motile cells to accommodate modified cytoskeletal architecture. In summary, these findings not only identify a novel mechanism for regulating RhoC expression but also advance p38γ as a candidate therapeutic target.

p38γ Mitogen-activated Protein Kinase (MAPK) Confers Breast Cancer Hormone Sensitivity by Switching Estrogen Receptor (ER) Signaling from Classical to Nonclassical Pathway via Stimulating ER Phosphorylation and c-Jun Transcription

“…In this cohort of 81 breast cancer specimens, 70.5% of tumors had increased p38␥ expression, 21.3% had no change, and 8.2% had decreased p38␥ expression relative to the matched controls. These results are consistent with previous reports from us and others (23,31,32). Importantly, levels of p38␥ were increased significantly in ER-negative (ER Ϫ ) and in PR-negative (PR Ϫ ) specimens compared with their receptor-positive counterparts ( Fig.…”

“…In addition, recent studies from others (28) and us (29) have shown that p38␥ can be selectively activated by certain stress stimuli, indicating its specific role in stress response. Because all MAPKs can phosphorylate the S/TP motif (30) such as Ser-118 in ER (10), p38␥ can stimulate breast cancer invasion and/or metastasis through binding and antagonizing ER (23), and/or additional pathways (31,32), p38␥ may therefore be a key MAPK to phosphorylate ER/Ser-118 in breast cancer (22). Moreover, p38␥ can increase c-Jun transcriptional activity through increasing c-Jun levels and by enhancing AP-1-dependent transcription (33).…”

UM-164: A Potent c-Src/p38 Kinase Inhibitor with In Vivo Activity against Triple-Negative Breast Cancer

“…Dual inhibition of c-Src and p38 kinases p38MAPK kinase activity is reported to have an important role in the metastasis of TNBC tumors (37). Thus, we hypothesized that UM-164's ability to potently inhibit the p38 kinases is beneficial with regard to the observed anti-TNBC activities.…”

Tumor cell migration screen identifies SRPK1 as breast cancer metastasis determinant

“…Alternatively, activation of TGF-β receptor induces the transition of otherwise poorly migratory epithelial cancer cells into migratory mesenchymal cells (7). Downstream effectors, such as the Rho-GTPase family member RhoC, further stimulate invasiveness and cancer cell dissemination (8). Similarly, integrin adhesome molecules such as integrin α 5 β 1 , focal adhesion kinase (FAK), Src, and p130Cas were shown to be associated with metastatic activity (9)(10)(11)(12)(13)(14).…”