Bortezomib suppresses TGF-β1-mediated LOXL4 reduction through the inhibition of MEK/ERK pathways in MDA-MB-231 cells

Lysyl oxidase (LOX), a copper-containing secretory oxidase, plays a key role in the regulation of extracellular stiffness through cross-linking with collagen and elastin. Among the LOX family of enzymes, LOX-like 4 (LOXL4) exhibits pro-tumor and anti-tumor properties; therefore, the functional role of LOXL4 in tumor progression is still under investigation. Here, we first determined that transforming growth factor-β1 (TGF-β1) significantly decreased LOXL4 expression in human breast cancer MDA-MB-231 cells, which suggested that decreased LOXL4 may participate in tumor progression. In this study, we also investigated how TGF-β1 decreases LOXL4 expression. TGF-β1-induced intracellular reactive oxygen species (ROS) played a role in LOXL4 protein expression but had no effect on LOXL4 mRNA levels. The proteasomal inhibitor, bortezomib, significantly suppressed TGF-β1-mediated LOXL4 reduction, which indicated that TGF-β1 facilitates LOXL4 proteasomal degradation. Furthermore, bortezomib inhibited TGF-β1-induced MEK/ERK pathways which are involved in LOXL4 reduction and TGF-β1-mediated cell migration. Finally, we also determined the potential role of N-glycosylation in LOXL4 secretion. We found that the dysregulation of N-glycosylation may be involved in the reduction in LOXL4 secretion. Overall, bortezomib is expected to inhibit TNBC progression by inhibiting both the MEK/ERK and proteasomal degradation pathways, which regulate LOXL4 expression.