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Epac (RAPGEF3) promotes betaglycan expression to mediate ciprofloxacin-induced suppression of cancer cell migration and metastasis: Mechanistic insights and drug repurposing potential

Year: 2025
Type: article
Abstract: Fluoroquinolones (FQs), potent antimicrobials, have shown potential in curbing cancer invasion and metastasis by affecting cell migration and extracellular matrix reshaping. However, the molecular mechanisms behind their impact remain unclear. The type III TGF-β receptor (TβR3, also called betaglycan), a co-receptor in the TGF-β superfamily, is often found to be downregulated in various human cancers. This receptor plays a crucial role in suppressing cancer progression and metastasis, independent of TGF-β signaling. In this study, we investigated the effects of ciprofloxacin (a member of FQs) on TβR3 production in cancer cells and their subsequent impact on cancer cell migration and invasion. Our results demonstrated that ciprofloxacin and other FQs dose-dependently elevated TβR3 levels, which was associated with reduced cell migration and invasion. Gene silencing and pharmacological approaches confirmed that exchange protein directly activated by cAMP (Epac) and JNK/AP1 pathways are critical for FQ-induced TβR3 expression. In vivo studies showed that mice receiving clinically relevant doses of ciprofloxacin exhibited elevated TβR3 levels in the liver and lung, which were associated with inhibited tumor progression. Furthermore, histological analysis of human non-small cell lung cancer (NSCLC) tissues revealed that metastatic lung cancers had lower TβR3 protein expression compared to matched normal lung tissues. Overall; our findings indicate that cancer invasion and malignancy are associated with reduced TβR3 levels, and that FQs can inhibit cancer cell migration and invasion by upregulating TβR3 expression. These results elucidate the potential for repositioning FQs as a supplemental therapeutic strategy in cancer treatment.
DOI: 10.1016/j.biopha.2025.118261
Authors: Hui-Pu Liu, Shun-Ban Tai, Jun-Lin Jiang, Shu-Farn Tey, Pei-Feng Liu, Ming-Wei Lin, Shuen-Chiu Wu, Yung-Che Chen, Chun-Lin Chen
Institutions: Zuoying Armed Forces General Hospital, Kaohsiung Armed Forces General Hospital, National Sun Yat-sen University, Chi Mei Medical Center, Kaohsiung Medical University, E-Da Hospital, Chang Gung University, Kaohsiung Chang Gung Memorial Hospital
Language: English
Open Access status: gold
Estimated APC paid: $3,610
OpenAlex ID: W4411361027
FWCI:
Cites: 55
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Related to: 10