Fluoroquinolones Suppress TGF-β and PMA-Induced MMP-9 Production in Cancer Cells: Implications in Repurposing Quinolone Antibiotics for Cancer Treatment

Background: Fluoroquinolones (FQs) are potent antimicrobials with multiple effects on host cells and tissues. Although FQs can attenuate cancer invasion and metastasis, the underlying molecular mechanisms remain unclear. Matrix metalloproteinase-9 (MMP-9) has functional roles in tumor angiogenesis,...

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Autores principales:	Cheng-Yi Huang, Jenq-Lin Yang, Jih-Jung Chen, Shun-Ban Tai, Yu-Hsuan Yeh, Pei-Feng Liu, Ming-Wei Lin, Chih-Ling Chung, Chun-Lin Chen
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	fluoroquinolones matrix metalloproteinase-9 TGF-β EMT Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/9f233283ac8f4dcf924677436de4d6ef
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spelling	oai:doaj.org-article:9f233283ac8f4dcf924677436de4d6ef2021-11-11T17:04:51ZFluoroquinolones Suppress TGF-β and PMA-Induced MMP-9 Production in Cancer Cells: Implications in Repurposing Quinolone Antibiotics for Cancer Treatment10.3390/ijms2221116021422-00671661-6596https://doaj.org/article/9f233283ac8f4dcf924677436de4d6ef2021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11602https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Background: Fluoroquinolones (FQs) are potent antimicrobials with multiple effects on host cells and tissues. Although FQs can attenuate cancer invasion and metastasis, the underlying molecular mechanisms remain unclear. Matrix metalloproteinase-9 (MMP-9) has functional roles in tumor angiogenesis, invasion, and metastasis, and is associated with cancer progression and poor prognosis, suggesting that inhibitors of MMP-9 activity and transcription are prime candidates for cancer therapy. Despite numerous preclinical data supporting the use of MMP-9 inhibitors as anticancer drugs, the few available examples are not therapeutically useful due to low specificity and off-target effects. We examined the effects of FQs on MMP-9 production in cancer cells following transforming growth factor beta (TGF-β) and phorbol 12-myristate 13-acetate (PMA) stimulation. Experimental approaches: Using confluent cultures of HepG2 and A549 cells, the effects of FQs (ciprofloxacin, levofloxacin, clinafloxacin, gatifloxacin, and enrofloxacin) on TGF-β and PMA-induced MMP-9 mRNA expression and production were studied in RNA extracts and culture supernatants, respectively. FQs specifically abrogated TGF-β and PMA-induced MMP-9 levels and activity in a concentration and time-dependent manner, without affecting other MMPs or proteins involved in epithelial-mesenchymal transition. Additionally, FQs inhibited TGF-β and PMA-induced cell migration via p38 and cyclic AMP signaling pathways. Conclusions and implications: Overall, we demonstrated that FQs inhibit cancer cell migration and invasion by downregulating MMP-9 expression and revealed the cellular mechanisms underlying their potential value in cancer treatment.Cheng-Yi HuangJenq-Lin YangJih-Jung ChenShun-Ban TaiYu-Hsuan YehPei-Feng LiuMing-Wei LinChih-Ling ChungChun-Lin ChenMDPI AGarticlefluoroquinolonesmatrix metalloproteinase-9TGF-βEMTBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11602, p 11602 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	fluoroquinolones matrix metalloproteinase-9 TGF-β EMT Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	fluoroquinolones matrix metalloproteinase-9 TGF-β EMT Biology (General) QH301-705.5 Chemistry QD1-999 Cheng-Yi Huang Jenq-Lin Yang Jih-Jung Chen Shun-Ban Tai Yu-Hsuan Yeh Pei-Feng Liu Ming-Wei Lin Chih-Ling Chung Chun-Lin Chen Fluoroquinolones Suppress TGF-β and PMA-Induced MMP-9 Production in Cancer Cells: Implications in Repurposing Quinolone Antibiotics for Cancer Treatment
description	Background: Fluoroquinolones (FQs) are potent antimicrobials with multiple effects on host cells and tissues. Although FQs can attenuate cancer invasion and metastasis, the underlying molecular mechanisms remain unclear. Matrix metalloproteinase-9 (MMP-9) has functional roles in tumor angiogenesis, invasion, and metastasis, and is associated with cancer progression and poor prognosis, suggesting that inhibitors of MMP-9 activity and transcription are prime candidates for cancer therapy. Despite numerous preclinical data supporting the use of MMP-9 inhibitors as anticancer drugs, the few available examples are not therapeutically useful due to low specificity and off-target effects. We examined the effects of FQs on MMP-9 production in cancer cells following transforming growth factor beta (TGF-β) and phorbol 12-myristate 13-acetate (PMA) stimulation. Experimental approaches: Using confluent cultures of HepG2 and A549 cells, the effects of FQs (ciprofloxacin, levofloxacin, clinafloxacin, gatifloxacin, and enrofloxacin) on TGF-β and PMA-induced MMP-9 mRNA expression and production were studied in RNA extracts and culture supernatants, respectively. FQs specifically abrogated TGF-β and PMA-induced MMP-9 levels and activity in a concentration and time-dependent manner, without affecting other MMPs or proteins involved in epithelial-mesenchymal transition. Additionally, FQs inhibited TGF-β and PMA-induced cell migration via p38 and cyclic AMP signaling pathways. Conclusions and implications: Overall, we demonstrated that FQs inhibit cancer cell migration and invasion by downregulating MMP-9 expression and revealed the cellular mechanisms underlying their potential value in cancer treatment.
format	article
author	Cheng-Yi Huang Jenq-Lin Yang Jih-Jung Chen Shun-Ban Tai Yu-Hsuan Yeh Pei-Feng Liu Ming-Wei Lin Chih-Ling Chung Chun-Lin Chen
author_facet	Cheng-Yi Huang Jenq-Lin Yang Jih-Jung Chen Shun-Ban Tai Yu-Hsuan Yeh Pei-Feng Liu Ming-Wei Lin Chih-Ling Chung Chun-Lin Chen
author_sort	Cheng-Yi Huang
title	Fluoroquinolones Suppress TGF-β and PMA-Induced MMP-9 Production in Cancer Cells: Implications in Repurposing Quinolone Antibiotics for Cancer Treatment
title_short	Fluoroquinolones Suppress TGF-β and PMA-Induced MMP-9 Production in Cancer Cells: Implications in Repurposing Quinolone Antibiotics for Cancer Treatment
title_full	Fluoroquinolones Suppress TGF-β and PMA-Induced MMP-9 Production in Cancer Cells: Implications in Repurposing Quinolone Antibiotics for Cancer Treatment
title_fullStr	Fluoroquinolones Suppress TGF-β and PMA-Induced MMP-9 Production in Cancer Cells: Implications in Repurposing Quinolone Antibiotics for Cancer Treatment
title_full_unstemmed	Fluoroquinolones Suppress TGF-β and PMA-Induced MMP-9 Production in Cancer Cells: Implications in Repurposing Quinolone Antibiotics for Cancer Treatment
title_sort	fluoroquinolones suppress tgf-β and pma-induced mmp-9 production in cancer cells: implications in repurposing quinolone antibiotics for cancer treatment
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/9f233283ac8f4dcf924677436de4d6ef
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Fluoroquinolones Suppress TGF-β and PMA-Induced MMP-9 Production in Cancer Cells: Implications in Repurposing Quinolone Antibiotics for Cancer Treatment

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