MEK1 Inhibitor Combined with Irradiation Reduces Migration of Breast Cancer Cells Including miR-221 and ZEB1 EMT Marker Expression

Abstract

The miR-221 expression is dependent on the oncogenic RAS-RAF-MEK pathway activation and influences epithelial-to-mesenchymal transition (EMT). The Cancer Genome Atlas (TCGA) database analysis showed high gene significance for ZEB1 with EMT module analysis and miR-221 overexpression within the triple-negative breast cancer (TNBC) and HER2+ subgroups when compared to luminal A/B subgroups. EMT marker expression analysis after MEK1 (TAK-733) inhibitor treatment and irradiation was combined with miR-221 and ZEB1 expression analysis. The interaction of miR-221 overexpression with irradiation and its influence on migration, proliferation, colony formation and subsequent EMT target activation were investigated. The results revealed that MEK1 inhibitor treatment combined with irradiation could decrease the migratory potential of breast cancer cells including reduction of miR-221 and corresponding downstream ZEB1 (EMT) marker expression. The clonogenic survival assays revealed that miR-221 overexpressing SKBR3 cells were more radioresistant when compared to the control. Remarkably, the effect of miR-221 overexpression on migration in highly proliferative and highly HER2-positive SKBR3 cells remained constant even upon 8 Gy irradiation. Further, in naturally miR-221-overexpressing MDA-MB-231 cells, the proliferation and migration significantly decrease after miR-221 knockdown. This leads to the assumption that radiation alone is not reducing migration capacity of miR-221-overexpressing cells and that additional factors play an important role in this context. The miR-221/ZEB1 activity is efficiently targeted upon MEK1 inhibitor (TAK-733) treatment and when combined with irradiation treatment, significant reduction in migration of breast cancer cells was shown.

Combining HDAC and MEK Inhibitors with Radiation against Glioblastoma-Derived Spheres

“…The MAPK pathway is activated by a series of phosphorylation events that can be targeted through MEK, the downstream activator of MAPK. Trametinib and TAK-733 are small-molecule-selective MEK inhibitors with antitumor activity in cancers, such as gliomas, multiple myeloma, melanoma and triple-negative breast cancer [ 8 , 9 , 10 , 11 , 12 ]. Trametinib has recently been applied in clinical studies of brain tumors, suggesting that it has the ability to cross the blood–brain barrier (BBB) [ 13 , 14 ].…”

Radiation-Induced Overexpression of TGFβ and PODXL Contributes to Colorectal Cancer Cell Radioresistance through Enhanced Motility

“…One study reported that radiation combined with an inhibitor of K-Ras/c-Raf/p38 signaling eliminated the metastatic potential of cervical cancers cells [28]. In addition, IR combined with treatment using a mitogen-activated protein kinase 1 inhibitor showed reduced breast-cancer cell migration [29]. For CRC, the pharmacological inhibition of phosphoinositide 3-kinase/AKT was shown to markedly enhance the cytotoxic effects of IR both in vitro and in vivo [30].…”

miR221 regulates cell migration by targeting annexin a1 expression in human mesothelial MeT-5A cells neoplastic-like transformed by multi-walled carbon nanotube

“…MiRNAs have been implicated in regulating the development and metastasis of human cancers. MiR221 is reported to be an oncogene in multiple cancers, including bladder cancer, breast cancer and thyroid cancer tumor cells [ 14 – 16 ]. The high expression of miR221 was correlated with the proliferation, invasion, and malignancy of thyroid cancer tumor cells [ 15 ].…”

“…The high expression of miR221 was correlated with the proliferation, invasion, and malignancy of thyroid cancer tumor cells [ 15 ]. The miR221/ZEB1 activity is efficiently targeted upon MEK1 inhibitor (TAK-733) treatment and when combined with irradiation treatment, significant reduction in migration of breast cancer cells was shown [ 16 ]. Likewise, in our study, miR221 expression was significant altered, and bioinformatic analysis revealed that annexin a1 might be a target for miR221 regulation.…”