NF-κB and neutrophil extracellular traps cooperate to promote breast cancer progression and metastasis

Journal Article · Sun Aug 15 04:00:00 EDT 2021 · Experimental Cell Research

DOI:https://doi.org/10.1016/J.YEXCR.2021.112707· OSTI ID:23195575

Zhu, Baoling; Zhang, Xi; Sun, Shuangshuang; Fu, Yimou; Xie, Lihua ^[1]; Ai, Peng ^[2]

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1. Department of Chemotherapy and Radiotherapy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000 (China)
2. Department of Vascular Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000 (China)

Highlights: • Cancer cells–derived factors, such as IL-8 and G-CSF, induce NETs formation via PAD4 and NF-κB. • NETs increase the interaction of NEMO with IKKα/β and enhance NF-κB activation. • Blockade of NETs using PAD4 inhibitor decreases NF-κB and tumor metastasis. • Selective inhibition of NF-κB reduces NETs formation and tumor growth and metastasis. Aberrant NF-κB activation and neutrophil extracellular traps (NETs) are associated with breast cancer progression. How NF-κB and NETs modulate each other in breast cancer development remains unclear. Here, we found that NETs induced by phorbol 12-myristate 13-acetate promote breast cancer cell progression. In turn, cancer cells–derived factors, such as IL-8 and granulocyte colony-stimulating factor, stimulate neutrophils to form NETs. Mechanistically, NETs increased the interaction of NF-κB essential modifier (NEMO) with IκB kinase (IKK)α/β and enhanced NF-κB activation. We then employed a cell-permeable peptide corresponding to the NEMO-binding domain (NBD) of IKKα/β, termed NBD peptide, which disrupts NETs-mediated NEMO interaction with IKKα/β and abolished NF-κB activation in vitro. NBD peptide also reduced IL-8 level and NETs formation, and suppressed primary tumor growth and/or lung metastasis in human breast cancer mouse xenograft models and mouse spontaneous breast cancer model. Blockade of NET formation using a peptidylarginine deiminase 4 (PAD4) pharmacologic inhibitor decreased NF-κB activation and tumor metastasis. Collectively, these data suggest that NF-κB associates with NETs to form a positive loop facilitating breast tumor progression and metastasis, and that selective inhibition of NF-κB and PAD4-dependent NETs provides an effective therapeutic approach for treating breast cancer.

• OSTI ID: 23195575
• Journal Information: Experimental Cell Research, Journal Name: Experimental Cell Research Journal Issue: 2 Vol. 405; ISSN 0014-4827; ISSN ECREAL
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ACETATES
IN VITRO
LUNGS
MAMMARY GLANDS
METASTASES
MICE
NEOPLASMS
NEUTROPHILS
PEPTIDES
PHOSPHOTRANSFERASES