# The Potential Role of Timosaponin-AIII in Cancer Prevention and Treatment
## 4 The Anticancer Effects of TSAIII
### Suppression of Migration and Invasion  
Metastasis is a complex process that includes the invasion/metastasis cascade [64]. Integrins, constituted by \(\upalpha\) and \(\upbeta\) subunits, interact with the extracellular matrix (ECM) and trigger the recruitment of actin filaments and their related factors in signaling pathways to integrins. Vital factors, such as focal adhesion kinase (FAK), AKT, Rho GTPase, and the Src family kinase, are activated [65]. The reorganization of actin filaments mediates downstream factors, such as cofilin, LIM domain kinase (LIMK), and testis-associated actin remodeling kinase 1 (TESK1) [66]. It has been reported that TSAIII could significantly reduce the expression and distribution of F-actin, which plays a key role in cancer cell migration and invasion. Mechanically, TSAIII suppresses the invasion of human osteosarcoma cells by downregulating the expression of integrin-\(\upalpha\), integrin-\(\upbeta\)3, and the phosphorylation of FAK/Src and upregulating the expression of TESK1 and the phosphorylation of cofilin, which results in the destruction of the F-actin cytoskeleton [67]. Cyclooxygenase (COX) has two isoforms, COX-1 and COX-2. COX-1 plays a key role in maintaining cellular homeostasis; COX-2 is an inducible enzyme that can be associated with inflammation, invasion, and migration [68]. It has been reported that the overexpression of COX-2 and its metabolite PGE2 promotes tumor progression and metastasis [69]. TSAIII treatment may result in the inhibition of cell migration by inhibiting the NF-\(\upkappa\)B signaling pathway and downregulating the expression of COX-2, PGE2, and PGE2 receptors (EP2 and EP4) in B16-F10 cells [70] (Table 1) (Figure 4). CTSC, as a cysteine protease in the cathepsin family, can be highly correlated with tumor metastasis. TSAIII has been reported to inhibit cell viability, migration, and invasion by suppressing the/AKT signaling and downregulating the CTSC expression in renal carcinoma 786-O and A-498 cells. CTSC can be a direct target of miR-129-5p, and both the specific PI3K inhibitor LY294002 and miR-129-5p can downregulate the expression of CTSC and inhibit the metastasis of 786-O and A-498 cells [71] (Table 1). Cervical cancer is the most common gynecologic tumor worldwide. The remodeling of ECM facilitates the migration and invasion of cancer cells, and the urokinase-type plasminogen activator (uPA) is the critical factor that is responsible for mediating ECM degradation [72]. TSAIII can inhibit migration and invasion by suppressing p38 MAPK signaling and uPA expression. The knockdown of p38 synergistically facilitates TSAIII-inhibited uPA expression and metastasis in human cervical cancer SiHa and HeLa cells. In addition, TSAIII significantly reduces the lung metastasis nodule number, lung weight, and tumor mass and improves pathological changes [73]. There are more than 20 MMPs that are responsible for the degradation of ECM. Among these, MMP-2 and MMP-9 are the two major enzymes for degrading gelatin. It has been reported that TSAIII downregulates the expression of MMP-2 and MMP-9 and inhibits the migration and invasion of human non-small-cell lung cancer A549 cells by attenuating the ERK1/2, Src/FAK, and \(\upbeta\)-catenin signaling pathways [74] (Table 1). B lymphoma Mo-MLV Insertion region 1 (BMI1), a polycomb group protein, is associated with the development of various malignancies, such as breast, leukemia, and prostate cancers [75]. The overexpression of BMI1 can result in bypassed cellular senescence and the increased replicative lifespan of cancer cells [76]. It has been reported that TSAIII can be an inhibitor of BMI1, inhibiting oncogenic phenotypes, such as proliferation, migration, and invasion, and inducing cellular senescence in MDA-MB-231 and MCF7 cells. In addition, TSAIII upregulates the expression of miR-200c and miR-141, which are tumor suppressors that are negatively mediated by BMI1 [77].