Target therapy of TRIM-14 inhibits osteosarcoma aggressiveness through the nuclear factor-κB signaling pathway

Abstract

Osteosarcoma is the most common cause of cancer-associated mortality and the prognosis is yet to be fully elucidated due to the paucity of effective therapeutic targets that significantly influence the quality of life and mean survival rates of patients with osteosarcoma. Studies have showed that tripartite motif-containing (TRIM)-14 is a member of the TRIM protein family that has a vital role in tumor progression and metastasis and promotes angiogenesis, invasion and apoptotic resistance of bone cancer. In this study, a chimeric antibody targeting TRIM-14 (Chanti-TRIM) was constructed and the molecular mechanism of target therapy for TRIM-14 was investigated in osteosarcoma cells and xenograft mice. The growth, migration and invasion properties of U-2OS cells were analyzed following incubation with 10–160 mg/ml Chanti-TRIM. Apoptosis of U-2OS cells was detected after Chanti-TRIM treatment. Matrix metalloproteinase (MMP)-9-mediated nuclear factor-κB (NF-κB) signal pathway was analyzed in U-2OS cells treated with Chanti-TRIM. The inhibitory efficacy of Chanti-TRIM was studied in U-2OS-bearing xenograft mice. Our results demonstrated that neutralizing TRIM-14 expression markedly inhibited the growth, migration and invasion of osteosarcoma cells, in vitro and in vivo. We found that TRIM-14 depletion decreased cell viability and induced cells apoptosis in vitro. In addition, we identified Chanti-TRIM inhibited growth and promoted apoptosis induced by cisplatin through MMP-9-mediated NF-κB signal pathway. Furthermore, we observed that Chanti-TRIM treatment inhibited osteosarcoma growth in vivo. Histological analysis indicated that apoptotic bodies were increased and NF-κB nuclear translocation factors, including Ikkβ, p65 and IkBα, were decreased in tumors treated by Chanti-TRIM. In conclusion, these results showed that Chanti-TRIM markedly inhibited the progression of osteosarcoma, suggesting Chanti-TRIM may be a potential anti-cancer agent that functions via the activation of the NF-κB pathway for osteosarcoma.

Tripartite Motif-Containing 46 Promotes Viability and Inhibits Apoptosis of Osteosarcoma Cells by Activating NF-B Signaling Through Ubiquitination of PPAR

“…In recent years, many studies have shown that TRIM family proteins such as TRIM2 19 , TRIM21 8 , TRIM14 16 , TRIM44 20 , TRIM59 21 , and TRIM66 22 are known to be dysregulated and involved in the pathogenesis of OS. However, the biologic functions of most TRIM proteins in OS, including TRIM46, have not been well elucidated.…”

“…TRIM21 activates the NF-κB signaling pathway by inducing IKKβ ubiquitination 15 and increases the proliferation and chemoresistance of OS cells 8 . TRIM14 downregulation results in the inhibition of OS cell growth and promotes their apoptosis through NF-κB signaling pathway 16 . Furthermore, TRIM23 regulates PPARγ protein stability through atypical ubiquitin conjugation to PPARγ 17 .…”

The novel circ_0028171/miR-218-5p/IKBKB axis promotes osteosarcoma cancer progression

“…In addition, IKBKB [28,29] has been shown to take part in tumor growth via NF-κB activation and the phosphorylation-dependent inhibition of tumor suppressors. A previous study [30] indicated that the protein expression levels of IKBKB were remarkably decreased in U-2OS cells after treated with Chanti-TRIM, while TRIM induced the expression levels of p65, IKKβ and IκBα. The above finding suggested that Chanti-TRIM may impede the aggressive phenotypes via the MMP-9-induced NF-κB signaling pathway in vitro.…”

TRIM family contribute to tumorigenesis, cancer development, and drug resistance

“…In addition, TRIM46 acts as an oncogene in OS by interacting with and ubiquitinating PPARα (peroxisome proliferator-activated receptor α), leading to the activation of the NF-κB signaling pathway [ 251 ]. Activation of the NF-κB pathway is also positively correlated with TRIM52 [ 252 ], TRIM14 [ 253 ], and TRIM31 [ 254 ] and promotes cancer development in cancers. In NSCLC, TRIM13 behaves as a tumor suppressor through by negatively regulating the NF-κB pathway [ 255 ].…”