机构：[1]Department of Hand and Foot Surgery, Hospital Affiliated 5 to Nantong University, Taizhou People’s Hospital, Taizhou, China[2]Department of Orthopaedics, the SecondAffiliated Hospital of Soochow University, Suzhou, China[3]Department of Orthopaedics, Wujin Hospital Affiliated to Jiangsu University, Changzhou, China[4]Department ofOrthopaedics, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China[5]Department of Orthopedics, The First Affiliated Hospital of Nanjing MedicalUniversity, Nanjing, China
Sphingosine kinase 1 (SphK1) expression and activity are elevated in human osteosarcoma (OS) and is a promising target of therapy. SKI-V is a non-competitive and highly-efficient non-lipid SphK1 inhibitor. The potential anti-OS cell activity by the SphK1 inhibitor was studied here. In primary OS cells and immortalized cell lines, SKI-V robustly suppressed cell survival, growth and proliferation as well as cell mobility, and inducing profound OS cell death and apoptosis. The SphK1 inhibitor was however non-cytotoxic nor pro-apoptotic in human osteoblasts. SKI-V robustly inhibited SphK1 activation and induced accumulation of ceramides, without affecting SphK1 expression in primary OS cells. The SphK1 activator K6PC-5 or sphingosine-1-phosphate partially inhibited SKI-V-induced OS cell death. We showed that SKI-V concurrently blocked Akt-mTOR activation in primary OS cells. A constitutively-active Akt1 (ca-Akt1, S473D) construct restored Akt-mTOR activation and mitigated SKI-V-mediated cytotoxicity in primary OS cells. In vivo, daily injection of SKI-V potently suppressed OS xenograft tumor growth in nude mice. In SKI-V-administrated OS xenograft tissues, SphK1 inhibition, ceramide increase and Akt-mTOR inhibition were detected. Together, SKI-V exerts significant anti-OS activity by inhibiting SphK1 and Akt-mTOR cascades in OS cells.
基金：
The Scientific research project of
Changzhou Health Commission (QN201829) and the Clinical Technology Development
Foundation of Jiangsu University (JLY20180009).
第一作者机构：[1]Department of Hand and Foot Surgery, Hospital Affiliated 5 to Nantong University, Taizhou People’s Hospital, Taizhou, China
共同第一作者：
通讯作者：
推荐引用方式(GB/T 7714)：
Sun Xu,Shan Hua-jian,Yin Gang,et al.The anti-osteosarcoma cell activity by the sphingosine kinase 1 inhibitor SKI-V[J].CELL DEATH DISCOVERY.2022,8(1):doi:10.1038/s41420-022-00838-4.
APA：
Sun, Xu,Shan, Hua-jian,Yin, Gang,Zhang, Xiang-yang,Huang, Yu-min&Li, Hai-jun.(2022).The anti-osteosarcoma cell activity by the sphingosine kinase 1 inhibitor SKI-V.CELL DEATH DISCOVERY,8,(1)
MLA：
Sun, Xu,et al."The anti-osteosarcoma cell activity by the sphingosine kinase 1 inhibitor SKI-V".CELL DEATH DISCOVERY 8..1(2022)
