Down-regulation of Skp2 expression inhibits invasion and lung metastasis in osteosarcoma

Abstract

Osteosarcoma (OS), the most common primary cancer of bone, exhibits a high propensity for local invasion and distant metastasis. This study sought to elucidate the role of S phase kinase-associated protein (Skp2) in osteosarcoma invasion and metastasis and to explore flavokawain A (FKA), a natural chalcone from kava extract, as a potential Skp2 targeting agent for preventing osteosarcoma progression. Skp2 was found to be overexpressed in multiple osteosarcoma cell lines, including 5 standard and 8 primary patient-derived cell lines. Patients whose tumors expressed high levels of Skp2 sustained a significantly worse metastasis-free (p = 0.0095) and overall survival (p = 0.0013) than those with low Skp2. Skp2 knockdown markedly reduced in vitro cellular invasion and in vivo lung metastasis in an orthotopic mouse model of osteosarcoma. Similar to Skp2 knockdown, treatment with FKA also reduced Skp2 expression in osteosarcoma cell lines and blocked the invasion of osteosarcoma cells in vitro and lung metastasis in vivo. Together, our findings suggest that Skp2 is a promising therapeutic target in osteosarcoma, and that FKA may be an effective Skp2-targeted therapy to reduce osteosarcoma metastasis.

Identification of key biomarkers and functional pathways in osteosarcomas with lung metastasis: Evidence from bioinformatics analysis

“…Furthermore, SKP2 has also been proven to enhance tumor invasion ability by promoting epithelial-mesenchymal transition (EMT) process and matrix metalloproteinase (MMP) expression [37,38] . Based on these encouraging results, Zhang et al found knockdown of Skp2 could result in RhoA and MMP-9 inhibition, thereby signi cantly reducing tumor cell invasion and lung metastasis in an orthotopic mouse model of osteosarcoma [39] . Not only that, SKP2 has also been reported to exert an effect in DNA damage response, DNA repair, tumor angiogenesis and drug resistance [40,41] .…”

“…Due to the extensive carcinogenic effects of SKP2, research on the anti-tumor activity of SKP2 small molecule inhibitors is in full swing. Among them, avokawain A (FKA), an effective apoptotic inducer and antiproliferative agent in the tumor, which could lead to down-regulation of SKP2, result in osteosarcoma growth retardation and metastasis inhibition [39] . However, more preclinical and clinical trials are necessary to explore the application of the speci c SKP2 inhibitors in the treatment of osteosarcoma with lung metastasis.…”

Kava as a Clinical Nutrient: Promises and Challenges

“…Recent reports have documented the anticancer activity of chalcone-based flavokavain A in various cancer cell culture models. For example, flavokavain A was reported to inhibit cancer progression in taxol-resistant cancer cells [ 119 ], inhibit cancer cell proliferation and metastasis [ 120 ], and induce apoptosis [ 121 ], autophagy, and G2/M cell cycle arrest [ 22 , 122 , 123 ]. It was also reported to enhance antitumor immunity [ 124 ] and synergize with chemotherapies [ 125 ].…”

“…It suppressed bladder cancer (T24) growth in a xenograft mouse model (50 mg/kg/d) [ 121 ]. At 200 mg/kg/d, flavokavain A inhibited lung metastasis of osteosarcoma cells in mice potentially via reducing Skp2 expression [ 120 ]. Lastly, flavokavain A was reported to enhance antitumor immunity and suppress the inflammatory process in breast cancer-challenged mice (50 mg/kg/d) [ 124 ].…”

Skp2 modulates proliferation, senescence and tumorigenesis of glioma

“…An increase in p27 Kip1 has been found to significantly reduce Mixed-Lineage Leukemia self-renewal ability, promote the monocytic differentiation of leukemic blasts, and induce cell death [5]. Skp2 has shown important roles in the development and progression of tumors as it was found to be frequently overexpressed in various human malignancies like hepatocellular carcinoma, breast cancer, lung cancers, prostate cancer, and osteosarcoma [2,[6][7][8][9][10][11]. In hepatocellular carcinoma, Skp2 was identified at a significantly increased level compared with paired normal tissue, and was correlated with tumor grade, size, and metastases.…”