Targeting mutant TP53 as a potential therapeutic strategy for the treatment of osteosarcoma.

Abstract

Mutant TP53 is a promising therapeutic target in cancers. Considering the current challenges facing the clinical treatment of cancer, as well as the urgent need to identify novel therapeutic targets in osteosarcomas, we aimed to evaluate the clinical significance of mutant TP53 in osteosarcoma patients and to explore the therapeutic effect of targeting mutant TP53 in osteosarcomas. We performed a meta-analysis to investigate the relationship between mutant TP53 and the overall survival of patients with osteosarcoma. A CRISPR-Cas9 system and a TP53 inhibitor, NSC59984, were also used to specifically knock-out and inhibit mutant TP53 in the human osteosarcoma cell lines, KHOS, and KHOSR2. The meta-analysis demonstrated that mutations in the TP53 gene could be used to predict a poor 2-year survival in osteosarcoma patients. We also demonstrated that the expression of mutant TP53 in human osteosarcoma cell lines can be efficiently knocked-out using CRISPR-Cas9, and this decreased the proliferation, migration, and tumor formation activity of these osteosarcoma cells. Moreover, drug sensitivity to doxorubicin was increased in these TP53 knock-out osteosarcoma cells. NSC59984 also showed similar anti-tumor effects as CRISPR-Cas9 targeted TP53 in the osteosarcoma cells in vitro. We have also demonstrated that the knock-out or inhibition of mutant TP53 decreased the expression of the oncogene IGF-1R, anti-apoptotic proteins Bcl-2, and Survivin in osteosarcoma cells. Collectively, these results suggest that mutant TP53 is a promising therapeutic target in osteosarcomas. Therefore, further studies exploring novel strategies to target mutant TP53 may help improve the treatment outcomes of osteosarcoma patients in the clinic. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.

• Authors: Fan Tang, Li Min, Nicole A Seebacher, Xiaoyang Li, Yubin Zhou, Francis J Hornicek, Yuquan Wei, Chongqi Tu, Zhenfeng Duan
• Journal: Journal of orthopaedic research : official publication of the Orthopaedic Research Society (J Orthop Res) Vol. 37 Issue 3 Pg. 789-798 (03 2019) ISSN: 1554-527X [Electronic] United States
• PMID: 30667081 (Publication Type: Journal Article, Meta-Analysis, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Chemical References

• 1-(4-methylpiperazin-1-yl)-3-(5-nitrofuran-2-yl)prop-2-en-1-one
• Antibiotics, Antineoplastic
• Nitrofurans
• Piperazines
• TP53 protein, human
• Tumor Suppressor Protein p53
• Doxorubicin

Topics

• Antibiotics, Antineoplastic (therapeutic use)
• Bone Neoplasms (genetics, therapy)
• CRISPR-Cas Systems
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Doxorubicin (therapeutic use)
• Drug Resistance, Neoplasm
• Drug Synergism
• Genes, p53
• Genetic Therapy
• Humans
• Mutation
• Nitrofurans (pharmacology, therapeutic use)
• Osteosarcoma (genetics, therapy)
• Piperazines (pharmacology, therapeutic use)
• Tumor Suppressor Protein p53 (antagonists & inhibitors, genetics)