MAPK7 Regulates EMT Features and Modulates the Generation of CTCs

Abstract

Epithelial-to-Mesenchymal Transition (EMT) has been implicated in models of tumor cell migration, invasion and metastasis. In a search for candidate therapeutic targets to reverse this process, non-tumorigenic MCF10A breast epithelial cells were infected with an arrayed lentiviral kinome shRNA library and screened for either suppression or enhancement of a 26-gene EMT RNA signature. No individual kinase gene knockdown was sufficient to induce EMT. In contrast, grouped epithelial markers were induced by knockdown of multiple kinases, including mitogen activated protein kinase 7 (MAPK7). In breast cancer cells, suppression of MAPK7 increased E-cadherin (CDH1) expression and inhibited cell migration. In an orthotopic mouse model, MAPK7 suppression reduced the generation of circulating tumor cells (CTCs) and the appearance of lung metastases. Together, these observations raise the possibility that targeting kinases that maintain mesenchymal cell properties in cancer cells, such as MAPK7, may lessen tumor invasiveness. Implications Suppression of MAPK7 induces epithelial markers, reduces generation of circulating tumor cells and appearance of lung metastases.

Oncogenic signaling of MEK5-ERK5

“…TG02, a multi-kinase inhibitor that targets ERK5, has also been shown to be an efficacious anti-tumor agent in the multiple myeloma and breast cancer settings [37, 45]. Based on studies demonstrating that shRNA-mediated knockdown of ERK5 did not alter growth dynamics of triple-negative breast cancer xenografts [26, 75], the anti-proliferative effects have been proposed as an artifact of TG02 activity against CDK targets. However, partial silencing of ERK5 may not be sufficient to exert anti-tumor effects in certain cell lines.…”

“…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].…”

“…In another investigation using metastatic A549 cells, knockdown of ERK5 resulted in reduced protein expression of CDH1 and ZO-1, upregulation of snail family zinc finger 1 (SNAI1), CDH2, and VIM, and enhanced cell migration [86]. Contrary to these findings, a recent study utilizing the same lung cancer cell line cited EMT suppressive, or MET inducing, effects of ERK5 depletion, including increased levels of CDH1 and reduction in cell migration, through regulation of SNAI2 with no change observed in SNAI1 levels [75]. These morphogenetic changes were recapitulated in a highly aggressive mesenchymal breast cancer model where suppression of ERK5 induced an epithelial phenotype and decreased intravascular invasion, leading to significantly fewer circulating tumor cells (CTCs) derived from primary orthotopic xenografts and reduction of metastatic lesions [75].…”

The Landscape of Circulating Tumor Cell Research in the Context of Epithelial-Mesenchymal Transition

“…Suppression of MAPK7 kinase, responsible for maintaining mesenchymal cell properties in cancer cells, reduced the generation of CTCs and the appearance of lung metastases in a xenograft model of NOD scid gamma mice injected with the MDA-MB-231 BC cell line [170] . Forcing cancer cells in the mesenchymal state to revert to the epithelial one (MET) with forskolin or cholera toxin was shown to reduce the frequency of stem cell markers and increase their sensitivity to a range of drugs -doxorubicin, paclitaxel, proteasome inhibitors and MAPK/EGFR inhibitors [101] .…”

The MEK5/ERK5 signalling pathway in cancer: a promising novel therapeutic target

“…In fact, ERK5 activation leads to cell proliferation through modulation of CDKs and cyclin D1 [32,33], the epithelial-mesenchymal transition (EMT) [34,35], MET/HGF-induced migration [36], and integrin/FAK-mediated metastasis [37]. Remarkably, following knockdown of the MEK5/ERK5 pathway, tumour xenograft growth, metastasis, and the generation of tumour circulating cells was significantly reduced [35,38]. Nevertheless, in contrast with this body of data, a recent study reported that ERK5 expression was reduced in breast cancer tumour samples, correlating with a worse disease prognosis, and that ERK5 inhibition in MDA-MB-231 and Hs578 T breast cancer cell lines contributed to increased cell migration and invasion [39].…”