Upregulation of MEK5 by Stat3 promotes breast cancer cell invasion and metastasis

Abstract

Mitogen extracellular-signal-regulated kinase kinase 5 (MEK5) plays an important role in promoting cell proliferation and tumorigenesis. The aberrant expression of MEK5 has been reported in various malignant diseases including cancers of breast, prostate, lung, colorectal and brain. However, the function and regulation of MEK5 signaling pathway are ambiguous and remain elusive with respect to its oncogenic roles in various cancers, especially in the regulation of the initiation and progression of cancer invasion and metastasis. Ectopic expression of MEK5 or knockdown of MEK5 by shRNA with in vitro cell based models demonstrated the role of MEK5 in regulation of epithelial mesenchymal transition (EMT) and breast cancer invasion and metastasis. Here, we show that MEK5 upregulated by Stat3 promotes breast cancer cell invasion through EMT. Further study demonstrated that Stat3 could bind to promoter region of MEK5 and enhanced MEK5 transcription and expression. In addition, the phosphorylation of MEK5 significantly increased in breast cancer cells corresponding to metastatic capability of breast cancer cells. The depletion of MEK5 by shRNA significantly decreased breast cancer invasion. Ectopic expression of MEK5 could confer non-invasive breast cancer cells to become invasion capable cells. Moreover, the phosphorylation of Erk5, a MEK5-regulated downstream kinase, was also upregulated consistent with the increased level of active MEK5. Our studies provide insights into a molecular mechanism by which MEK5 transcriptionally upregulated by Stat3 augments breast cancer cell EMT, which subsequently enhances cancer cell invasion and metastasis. This finding may suggest that Stat3 and MEK5/Erk5 pathways could be an effective therapeutic target for inhibition of breast cancer invasion and metastasis.

Taoren Honghua Drug Attenuates Atherosclerosis and Plays an Anti-Inflammatory Role in ApoE Knock-Out Mice and RAW264.7 Cells

“…**P < 0.01 versus group without LPS and THD; ## P < 0.01 versus group with LPS only. (Liu et al, 2017). Thus, we investigated total and activated ERK5 and STAT3.…”

Oncogenic signaling of MEK5-ERK5

“…Molecular inhibition of ERK5 in vitro suppressed cell motility and invasion of liver, breast, and prostate cancer cells [63, 82] and decreased metastasis of breast cancer xenografts in vivo [26, 75]. Conversely, cancer cells overexpressing MEK5 or ERK5 exhibited a migratory and invasive phenotype [66, 74], denoted by an increase in tumor metastases [67, 77, 83]. …”

The MEK5–ERK5 Kinase Axis Controls Lipid Metabolism in Small-Cell Lung Cancer

“…[15][16][17]. This dual kinase axis is responsible for increased growth or metastasis, lower overall survival, or resistance to therapies in multiple tumor types, including breast cancer (16,(18)(19)(20), prostate cancer (21), colon cancer (18), hepatocellular carcinomas (18,21), and high-grade osteosarcomas (18). Overall, however, the molecular mechanisms and intracellular consequences of MEK5 and ERK5 actions leading to these cancer phenotypes are not well understood.…”