Recent findings have revealed the role of membrane traffic in the signaling of transforming growth factor-β (TGF-β). These findings originate from the pivotal function of TGF-β in development, cell proliferation, tumor metastasis, and many other processes essential in malignancy. Actin and unconventional myosin have crucial roles in subcellular trafficking of receptors; research has also revealed a growing number of unconventional myosins that have crucial roles in TGF-β signaling. Unconventional myosins modulate the spatial organization of endocytic trafficking and tether membranes or transport them along the actin cytoskeletons. Current models do not fully explain how membrane traffic forms a bridge between TGF-β and the downstream effectors that produce its functional responsiveness, such as cell migration. In this review, we present a brief overview of the current knowledge of the TGF-β signaling pathway and the molecular components that comprise the core pathway as follows: ligands, receptors, and Smad mediators. Second, we highlight key role(s) of myosin motor-mediated protein trafficking and membrane domain segregation in the modulation of the TGF-β signaling pathway. Finally, we review future challenges and provide future prospects in this field.

Cembrane-type diterpenoids (cembranoids), natural compounds derived from soft coral Sclerophytum flexibile, exhibit diverse biological activities including anti-inflammatory, anti-cancer, and anti-viral effects. Our previous research demonstrated that Sinulariolide, a member of this group, effectively inhibits TGF-β-induced IL-6 secretion, thereby suppressing inflammation-associated cancer development. Building on these findings, the present study employs a structure-activity relationship (SAR) approach to compare the anti-inflammatory properties of various cembranoids extracted from cultured soft coral Sclerophytum flexibile—a sustainable and environmentally friendly source that offers a consistent supply for research and therapeutic development. By isolating multiple cembrane-type analogs and analyzing their structural differences, we identified key chemical features that enhance their ability to interfere with TGF-β signaling and subsequent IL-6 production. The SAR analysis revealed distinct variations in anti-inflammatory efficacy among the tested compounds, pinpointing structural motifs crucial for inhibiting TGF-β-induced IL-6 secretion. These insights deepen our understanding of the molecular basis behind the anti-inflammatory action of cembranoids and guide the optimization of these compounds for potential therapeutic use.

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.