Potential Antimetastatic Effect of Timosaponin AIII against Human Osteosarcoma Cells through Regulating the Integrin/FAK/Cofilin Axis

Abstract

Timosaponin AIII (TSAIII) is a steroidal saponin which demonstrates anti-tumour activities. However, the effect of TSAIII on human osteosarcoma cells remains largely unknown. In this study, we demonstrated that TSAIII exerted a significant inhibitory effect on the distribution of cytoskeletal F-actin and cytoskeletal-related proteins, which contributed to the suppression of cell migration and invasion, without inhibiting cell growth or apoptosis. In the synergistic inhibitory analysis, cotreatment of TSAIII with αVβ3 integrin inhibitor [Cyclo(RGDyK)] or focal adhesion kinase (FAK) inhibitor (PF-573228) exerted greater synergistic inhibitory effects on the expression of Intergin αVβ3/FAK/cofilin axis, thus inhibiting the migration and invasion capacities of human osteosarcoma cells. TSAIII was demonstrated to significantly inhibit the pulmonary metastasis formation of human osteosarcoma cells in vivo in metastasis animal models. These findings reveal the inhibitory effects of TSAIII on the metastasis progression of human osteosarcoma cells and the regulation of integrin-αVβ3-FAK-Src and TESK1/p-cofilin mediated cytoskeletal F-actin pathway. Therefore, TSAIII might represent a novel strategy for the auxiliary treatment of human osteosarcoma cells.

Angio-Associated Migratory Cell Protein (AAMP) Regulates the Hippo/YAP Pathway and Mitochondrial Functionality to Drive Osteosarcoma Metastasis

“…Mitochondria are key mediators of cellular energy production in the form of ATP (Foo et al, 2021), in uencing proliferative activity, apoptosis, and differentiation while also contributing to ROS generation, regulating calcium homeostasis, and coordinating signal transduction (Foo et (Hsieh et al, 2021). In light of our above results, we speculated that AAMP may regulate mitochondrial dynamics within OS cells.…”

Recent and Ongoing Research into Metastatic Osteosarcoma Treatments

“…Although these models are a powerful tool, it can be difficult to determine if a drug is active against established metastases unless researchers commence treatment after metastases have formed. Authors evaluating therapies such as 3-hydroxyflavone, euxanthone, CXCR4, Timosaponin, TRAIL, Panobinostat, mycophenolic acid, zoledronic acid, rapamycin, parthenolide or quercetin began treatment prior to the injection of cells or shortly afterwards [ 145 , 147 , 148 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 ]. In those studies, efficacy may reflect action against tumor cells within the circulation and/or growing in the lungs.…”

Osteosarcoma mechanobiology and therapeutic targets

“…Integrin overexpression contributes to OS invasion and angiogenesis by interacting with mechanotransductors ezrin and cofilin and influencing actin arrangement. A combination treatment of αVβ3 integrin inhibitor Cyclo (RGDyK) and Timosaponin AIII inhibited OS metastasis by disrupting F‐actin organization, decreasing integrin levels and deactivating cofilin (Hsieh et al, 2021 ). Deactivating cofilin would inhibit actin nuclear import and osteogenesis, which might explain the decreased proliferation and spread of OS cells.…”