6300

MAPK12

mitogen-activated protein kinase 12;MAPK12;mitogen-activated protein kinase 12

MAP kinase 12|MAP kinase p38 gamma|extracellular signal-regulated kinase 6|mitogen-activated protein kinase 3|mitogen-activated protein kinase p38 gamma|stress-activated protein kinase 3

22q13.33

protein-coding

p38gamma MAPK, one of the four members of p38 mitogen-activated protein kinases (MAPKs), has previously been shown to harbor oncogenic functions. However, the biologic function of p38gamma MAPK in breast cancer has not been well defined. In this study, we have shown that p38gamma MAPK is overexpressed in highly metastatic human and mouse breast cancer cell lines and p38gamma MAPK expression is preferentially associated with basal-like and metastatic phenotypes of breast tumor samples. Ectopic expression of p38gamma MAPK did not lead to an increase in oncogenic properties in vitro in most tested mammary epithelial cells. However, knockdown of p38gamma MAPK expression resulted in a dramatic decrease in cell proliferation, colony formation, cell migration, invasion in vitro and significant retardation of tumorigenesis, and long-distance metastasis to the lungs in vivo. Moreover, knockdown of p38gamma MAPK triggered the activation of AKT signaling. Inhibition of this feedback loop with various PI3K/AKT signaling inhibitors facilitated the effect of targeting p38gamma MAPK. We further found that overexpression of p38gamma MAPK did not promote cell resistance to chemotherapeutic agents doxorubicin and paclitaxel but significantly increased cell resistance to PJ-34, a DNA damage agent poly (ADP-ribose)-polymerase-1 (PARP) inhibitor in vitro and in vivo. Finally, we identified that p38gamma MAPK overexpression led to marked cell cycle arrest in G(2)/M phase. Our study for the first time clearly demonstrates that p38gamma MAPK is a promising target for the design of targeted therapies for basal-like breast cancer with metastatic characteristics and for overcoming potential resistance against the PARP inhibitor.

Understanding the molecular alterations that confer cancer cells with motile, metastatic properties is needed to improve patient survival. Here, we report that p38gamma motogen-activated protein kinase regulates breast cancer cell motility and metastasis, in part, by controlling expression of the metastasis-associated small GTPase RhoC. This p38gamma-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 showed that p38gamma-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 p38gamma is associated with lower overall survival of patients with breast cancer. Taken together, our results offer a detailed characterization of how p38gamma contributes to breast cancer progression. Herein we present a new mechanics-based analysis of cell motility, and report on the discovery of 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 p38gamma as a candidate therapeutic target.