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.

• Authors: Ying Zhao, Chao-Chao Ge, Jun Wang, Xiao-Xiao Wu, Xiao-Min Li, Wei Li, Sha-Sha Wang, Tong Liu, Jiu-Zhou Hou, Hua Sun, Dong Fang, Song-Qiang Xie
• Journal: Oncology reports (Oncol Rep) Vol. 38 Issue 5 Pg. 3055-3063 (Nov 2017) ISSN: 1791-2431 [Electronic] Greece
• PMID: 29048617 (Publication Type: Journal Article)

Chemical References

• CTNNB1 protein, human
• Flavonoids
• Protein Kinase Inhibitors
• beta Catenin
• EGFR protein, human
• ErbB Receptors
• MAP Kinase Kinase Kinases
• 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one

Topics

• Breast Neoplasms (drug therapy, genetics, pathology)
• Cell Movement (drug effects)
• Cell Nucleolus (drug effects)
• Cell Proliferation (drug effects)
• ErbB Receptors (genetics)
• Female
• Flavonoids (administration & dosage)
• Humans
• MAP Kinase Kinase Kinases (antagonists & inhibitors, genetics)
• MAP Kinase Signaling System (drug effects)
• MCF-7 Cells
• Protein Kinase Inhibitors (administration & dosage)
• beta Catenin (genetics)