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,...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-10-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/22/21/11602 |
| _version_ | 1797512441733578752 |
|---|---|
| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T06:01:51Z |
| format | Article |
| id | doaj.art-9f233283ac8f4dcf924677436de4d6ef |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T06:01:51Z |
| publishDate | 2021-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-9f233283ac8f4dcf924677436de4d6ef2023-11-22T20:54:53ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-10-0122211160210.3390/ijms222111602Fluoroquinolones Suppress TGF-β and PMA-Induced MMP-9 Production in Cancer Cells: Implications in Repurposing Quinolone Antibiotics for Cancer TreatmentCheng-Yi Huang0Jenq-Lin Yang1Jih-Jung Chen2Shun-Ban Tai3Yu-Hsuan Yeh4Pei-Feng Liu5Ming-Wei Lin6Chih-Ling Chung7Chun-Lin Chen8Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung 80424, TaiwanInstitute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, TaiwanDepartment of Pharmacy, School of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Linong Street, Taipei 11221, TaiwanDepartment of Biological Sciences, National Sun Yat-Sen University, Kaohsiung 80424, TaiwanDepartment of Biological Sciences, National Sun Yat-Sen University, Kaohsiung 80424, TaiwanDepartment of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung 80756, TaiwanDepartment of Chinese Medicine, E-Da Hospital, Kaohsiung 82445, TaiwanDepartment of Biological Sciences, National Sun Yat-Sen University, Kaohsiung 80424, TaiwanDepartment of Biological Sciences, National Sun Yat-Sen University, Kaohsiung 80424, TaiwanBackground: 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.https://www.mdpi.com/1422-0067/22/21/11602fluoroquinolonesmatrix metalloproteinase-9TGF-βEMT |
| spellingShingle | 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 International Journal of Molecular Sciences fluoroquinolones matrix metalloproteinase-9 TGF-β EMT |
| title | 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_short | 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 |
| topic | fluoroquinolones matrix metalloproteinase-9 TGF-β EMT |
| url | https://www.mdpi.com/1422-0067/22/21/11602 |
| work_keys_str_mv | AT chengyihuang fluoroquinolonessuppresstgfbandpmainducedmmp9productionincancercellsimplicationsinrepurposingquinoloneantibioticsforcancertreatment AT jenqlinyang fluoroquinolonessuppresstgfbandpmainducedmmp9productionincancercellsimplicationsinrepurposingquinoloneantibioticsforcancertreatment AT jihjungchen fluoroquinolonessuppresstgfbandpmainducedmmp9productionincancercellsimplicationsinrepurposingquinoloneantibioticsforcancertreatment AT shunbantai fluoroquinolonessuppresstgfbandpmainducedmmp9productionincancercellsimplicationsinrepurposingquinoloneantibioticsforcancertreatment AT yuhsuanyeh fluoroquinolonessuppresstgfbandpmainducedmmp9productionincancercellsimplicationsinrepurposingquinoloneantibioticsforcancertreatment AT peifengliu fluoroquinolonessuppresstgfbandpmainducedmmp9productionincancercellsimplicationsinrepurposingquinoloneantibioticsforcancertreatment AT mingweilin fluoroquinolonessuppresstgfbandpmainducedmmp9productionincancercellsimplicationsinrepurposingquinoloneantibioticsforcancertreatment AT chihlingchung fluoroquinolonessuppresstgfbandpmainducedmmp9productionincancercellsimplicationsinrepurposingquinoloneantibioticsforcancertreatment AT chunlinchen fluoroquinolonessuppresstgfbandpmainducedmmp9productionincancercellsimplicationsinrepurposingquinoloneantibioticsforcancertreatment |