Dissection of the Signal Transduction Machinery Responsible for the Lysyl Oxidase-like 4-mediated Increase in Invasive Motility in Triple-negative Breast Cancer Cells: Mechanistic Insight into the Integrin-β1-NF-κB-MMP9 Axis

Overview

Journal Front Oncol

Specialty Oncology

Date 2024 Jun 12

PMID 38863623

Authors

Fan Jiang

Youyi Chen

Nahoko Tomonobu

Rie Kinoshita

Ni Luh Gede Yoni Komalasari

Carlos Ichiro Kasano-Camones

Kazumi Ninomiya

Hitoshi Murata

Ken-Ichi Yamamoto

Yuma Gohara

Toshiki Ochi

I Made Winarsa Ruma

I Wayan Sumardika

Jin Zhou

Tomoko Honjo

Yoshihiko Sakaguchi

Akira Yamauchi

Futoshi Kuribayashi

Junichiro Futami

Eisaku Kondo

Yusuke Inoue

Shinichi Toyooka

Masakiyo Sakaguchi

Affiliations

Soon will be listed here.

Abstract

Background: Triple-negative breast cancer (TNBC) cells are a highly formidable cancer to treat. Nonetheless, by continued investigation into the molecular biology underlying the complex regulation of TNBC cell activity, vulnerabilities can be exposed as potential therapeutic targets at the molecular level. We previously revealed that lysyl oxidase-like 4 (LOXL4) promotes the invasiveness of TNBC cells via cell surface annexin A2 as a novel binding substrate of LOXL4, which promotes the abundant localization of integrin-β1 at the cancer plasma membrane. However, it has yet to be uncovered how the LOXL4-mediated abundance of integrin-β1 hastens the invasive outgrowth of TNBC cells at the molecular level.

Methods: LOXL4-overexpressing stable clones were established from MDA-MB-231 cells and subjected to molecular analyses, real-time qPCR and zymography to clarify their invasiveness, signal transduction, and matrix metalloprotease (MMP) activity, respectively.

Results: Our results show that LOXL4 potently promotes the induction of matrix metalloprotease 9 (MMP9) via activation of nuclear factor-κB (NF-κB). Our molecular analysis revealed that TNF receptor-associated factor 4 (TRAF4) and TGF-β activated kinase 1 (TAK1) were required for the activation of NF-κB through Iκβ kinase kinase (IKKα/β) phosphorylation.

Conclusion: Our results demonstrate that the newly identified LOXL4-mediated axis, integrin-β1-TRAF4-TAK1-IKKα/β-Iκβα-NF-κB-MMP9, is crucial for TNBC cell invasiveness.

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