MEK inhibitor, PD98059, promotes breast cancer cell migration by inducing β-catenin nuclear accumulation

Abstract

Abnormal activation of the RAF/MEK/ERK signaling pathway has been observed in breast cancer. Thus, a number of MEK inhibitors have been designed as one treatment option for breast cancer. Although some studies have found that these MEK inhibitors inhibit the growth of a variety of human cancer cells, some trials have shown that the use of MEK inhibitors as a treatment for breast cancer does not adequately improve survival for unknown reasons. In the present study, MEK inhibitor PD98059 was used to evaluate its anticancer effects on human breast cancer MCF-7 and MDA-MB-231 cells and to explore the possible mechanism of action. Our results revealed that MEK inhibitor PD98059 exhibited antiproliferative effects in a dose- and time-dependent manner in MCF-7 and MDA-MB-231 breast cancer cells. Conversely, incubation of MCF-7 and MDA-MB-231 cells with PD98059 promoted their migration. Further investigation disclosed that the enhanced ability of migration promoted by PD98059 was dependent on β-catenin nuclear translocation in the MCF-7 and MDA-MB‑231 cells. Subsequent experiments documented that activation of EGFR signaling induced by PD98059 increased the amount of β-catenin in the nucleus. Taken together, our findings may elucidate a possible mechanism explaining the ineffectiveness of MEK inhibitors in breast cancer treatment and improve our understanding of the role of MEK in cancer.

Effective Treatment of Metastatic Melanoma by Combining MAPK and PI3K Signaling Pathway Inhibitors

“…During constant exposure to the drugs in the scratch wound assay, buparlisib inhibited cell migration more than trametinib. Interestingly, it has previously been shown that a MEK inhibitor was able to promote cell migration, despite drug-induced cell death in a dose-dependent manner [36]. Concerning the trans-well assay, measuring cell migration towards a chemoattractant, pre-treating cells with trametinib seemed to inhibit cell migration more than buparlisib.…”

Suppression of epidermal growth factor receptor‐mediated β‐catenin nuclear accumulation enhances the anti‐tumor activity of phosphoinositide 3‐kinase inhibitor in breast cancer

“…EGFR usually performs its biological functions via activation of PLC‐γ1‐PKC, MAPK‐MEK‐ERK, and PI3K‐Akt‐mTOR signaling pathways (Lee et al, ; Huang et al, ). However, inhibition of these downstream pathway of EGFR often induces feedback activation of upstream multiple receptor tyrosine kinases (RTKs) and quick rebound of the pathway activity (Stratikopoulos et al, ; Zhao et al, ). Consistent with these reports, we found combination PI3K inhibitor LY294002 with tyrosine kinase inhibitor against EGFR produce an additive antiproliferative effect in breast cancer.…”

“…The total proteins from cancer cells were extracted using RIPA buffer as previous described (Zhao et al, ). The nuclear protein was isolated using the nuclear protein extraction kit (Beyotime, Shanghai, China) according to the manufacturer's instruction.…”

DKK1 inhibits breast cancer cell migration and invasion through suppression of β-catenin/MMP7 signaling pathway

“…The wound scratch assay was performed as previously described [17]. Cells were seeded in a 24-well plate and cultured, after cells had grown to confluence, a wound was scratched with a plastic tip and incubated for 24 h in RPMI 1640 medium.…”