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Updated: May 30, 2025
Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
Published on: October 27, 2020
Bortezomib suppresses TGF-β1-mediated LOXL4 reduction through the inhibition of MEK/ERK pathways in MDA-MB-231 cells
Tetsuro Kamiya1, Kana Ishii1, Kiyomi Ozawa1
1Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, Gifu, Japan.
Abstract:
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.
Insights
Transforming growth factor-β1 reduces lysyl oxidase-like 4 (LOXL4) in breast cancer cells via proteasomal degradation. Bortezomib inhibits this process and cell migration, suggesting a therapeutic strategy for triple-negative breast cancer (TNBC).
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Lysyl oxidase (LOX) enzymes regulate extracellular matrix stiffness by cross-linking collagen and elastin.
- LOX-like 4 (LOXL4) has context-dependent roles in tumor progression, necessitating further investigation.
- Transforming growth factor-β1 (TGF-β1) signaling is implicated in various cancers, including breast cancer.
Purpose of the Study:
- To investigate the effect of TGF-β1 on LOXL4 expression in human breast cancer cells.
- To elucidate the molecular mechanisms by which TGF-β1 regulates LOXL4 expression and secretion.
- To evaluate the potential of bortezomib as a therapeutic agent targeting LOXL4 regulation in triple-negative breast cancer (TNBC).
Main Methods:
- Treatment of MDA-MB-231 cells with TGF-β1 and bortezomib.
- Measurement of LOXL4 protein and mRNA levels.
- Assessment of reactive oxygen species (ROS) production.
- Analysis of proteasomal degradation pathways.
- Investigation of MEK/ERK signaling pathways.
- Evaluation of N-glycosylation and LOXL4 secretion.
Main Results:
- TGF-β1 significantly decreased LOXL4 protein expression in breast cancer cells.
- TGF-β1-induced ROS contributed to LOXL4 protein reduction, but not mRNA levels.
- Bortezomib inhibited TGF-β1-mediated LOXL4 proteasomal degradation and MEK/ERK pathway activation.
- Dysregulation of N-glycosylation may affect LOXL4 secretion.
- Bortezomib inhibited TGF-β1-induced cell migration.
Conclusions:
- TGF-β1 downregulates LOXL4 expression in breast cancer cells primarily through enhanced proteasomal degradation.
- Bortezomib can counteract TGF-β1 effects by inhibiting proteasomal degradation and MEK/ERK signaling, thereby reducing cell migration.
- Targeting LOXL4 regulation via bortezomib presents a potential therapeutic strategy for TNBC.
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