TIMP3 Overexpression Improves the Sensitivity of Osteosarcoma to Cisplatin by Reducing IL-6 Production

Abstract

Osteosarcoma is the most common bone cancer in children and adolescents. Tissue inhibitors of metalloproteinases (TIMPs)-3 inhibit matrix metalloproteinases to limit extracellular matrix degradation. Cisplatin is a widely used chemotherapeutic drug used to cure osteosarcoma. Interleukin (IL)-6 and TIMP3 play important roles in the drug resistance of osteosarcoma; however, their relationship in this process remains unclear. This study aimed to explore the role of TIMP3 in the cisplatin sensitivity of osteosarcoma and its underlying molecular mechanisms in vitro and in vivo. We compared TIMP3 expression levels between patients with cisplatin-sensitive and -insensitive osteosarcoma. TIMP3 was overexpressed or knocked down in the Saos2-lung cell line, which is a Saos2 subtype isolated from pulmonary metastases that has higher cisplatin chemoresistance than Saos2 cells. IL-6 expression, cell proliferation, sensitivity to cisplatin, migration, and invasion after TIMP3 overexpression or knockdown were determined. The same experiments were performed using MG63 and U2OS cells. Subsequently, luciferase-labeled Saos2-lung cells overexpressing TIMP3 were injected into the tibiae of nude mice treated with cisplatin. The results showed that IL-6 inhibited TIMP3 expression in Saos2 and Saos2-lung cells via signal transducer and activator of transcription 3 (STAT3) activation. STAT3 knockdown reversed the effect of IL-6. The expression of TIMP3 was higher in patients with cisplatin-sensitive osteosarcoma than in those with insensitive osteosarcoma. IL-6 expression was downregulated upon TIMP3 overexpression, and upregulated by TIMP3 knockdown. TIMP3 overexpression suppressed cell proliferation and enhanced cisplatin sensitivity by activating apoptosis-related signal pathways and inhibiting IL-6 expression in vitro and in vivo. In conclusion, cisplatin sensitivity correlated positively with TIMP3 expression, which is regulated by the IL-6/TIMP3/caspase pathway. The TIMP3 pathway could represent a target for new therapies to treat osteosarcoma.

IL-6 Promotes Cancer Stemness and Oncogenicity in U2OS and MG-63 Osteosarcoma Cells by Upregulating the OPN-STAT3 Pathway

“…Endogenous IL-6/IL-6-related signaling contribute to elevated proliferation/ chemoresistance of osteosarcoma cells, and induce their epithelial-to-mesenchymal transition (EMT), thus promoting their migration and invasion 20. Furthermore, Han et al reported that osteosarcoma cells become more sensitive to cisplatin when IL-6 production is reduced 21; however, little is known about the relationship between IL-6 expression and the clinicopathological characteristics of patients with osteosarcoma. Moreover, there are no data indicating whether IL-6 can modulate the malignant traits of osteosarcoma, including maintenance/promotion of stemness.…”

Fructose-coated Angstrom silver inhibits osteosarcoma growth and metastasis via promoting ROS-dependent apoptosis through the alteration of glucose metabolism by inhibiting PDK

“…We then generated subcutaneous 143B xenografts in nude mice, and compared the anti-tumor efficiency of F-AgÅPs and cisplatin (a first-line chemotherapeutic drug for osteosarcoma therapy) 32 against osteosarcoma in vivo . Figure 3 A shows the tumor sizes of 143B xenograft-bearing nude mice during an observation period of 21 days after intravenous injection of F-AgÅPs, cisplatin or solvent (normal saline).…”

Exosome-mediated transfer of MIF confers temozolomide resistance by regulating TIMP3/PI3K/AKT axis in gliomas

“…TIMP3, a member of the TIMP family, is a 24-kDa secreted glycoprotein and can suppress cell proliferation and enhance chemosensitivity by activating apoptosis-related signal pathways. [33][34][35][36][37] In addition, the analysis of TCGA and CGGA cohorts showed significant negative correlation between MIF and TIMP3 (Figure 5C). Further experiments verified that TIMP3 was upregulated at both mRNA and proteins levels after knockdown of MIF in TR cells (Figures 5D and 5E).…”

“…Jackson et al 44 reported that many mechanisms of preventing TIMP3 expression in diverse human cancers support that TIMP3 acts as a tumor suppressor. Han et al 37 reported that TIMP3 overexpression suppressed cell proliferation and enhanced cisplatin sensitivity by activating apoptosis-related signaling pathways. But, so far, the relationship between MIF and TIMP3 has not been reported yet.…”