Combined inhibition of MEK and FOXO1 synergistically suppresses MDA-MB-231 cell proliferation with reduced LOXL4.

Abstract

Triple-negative breast cancer (TNBC) is characterized by its aggressive phenotype and limited therapeutic options. FOXO1, a member of the O-class of forkhead transcription factors, has been implicated in various oncogenic processes, yet its specific role in TNBC remains to be fully elucidated. This study aimed to investigate the effects of the FOXO1-selective inhibitor, AS1842856, on the proliferation of the human TNBC cell line MDA-MB-231 and to identify the underlying molecular mechanisms. Treatment with AS1842856 significantly suppressed the proliferation of MDA-MB-231 cells in a dose-dependent manner. Additionally, AS1842856 suppressed the expression of lysyl oxidase-like 4 (LOXL4). Given LOXL4 is known to be involved in extracellular matrix remodeling and is frequently associated with cancer progression and metastasis, AS8142856 has been considered to suppress MDA-MB-231 cell migration. Interestingly, however, the knockdown of FOXO1 did not lead to a significant reduction in LOXL4 expression levels, suggesting that AS1842856 suppresses LOXL4 expression through FOXO1-independent mechanisms. We found that AS1842856-mediated ERK activation and intracellular reactive oxygen species are crucial in reducing LOXL4. Furthermore, the combined action of pharmacological inhibition of ERK pathways and AS1842856 suppressed MDA-MB-231 cell migration. These findings demonstrate that the ERK-LOXL4 signaling axis may play a critical role in the proliferation of TNBC cells. In conclusion, targeting the LOXL4 and ERK pathways pharmacologically could provide a novel therapeutic strategy for the treatment of aggressive breast cancers.