Celastrol increases osteosarcoma cell lysis by γδ T cells through up-regulation of death receptors
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Zhaoxu Li1, Junzhe Zhang1, Jicun Tang1, Ruiying Wang1
1Department of Orthopaedics, Affiliated Hospital, Guilin Medical University, Guilin, Guangxi, China
Ruiying Wang, email: [email protected]
Keywords: osteosarcoma, tripterine, TNF-related apoptosis-inducing ligand, immunotherapy
Received: January 17, 2016 Accepted: October 01, 2016 Published: October 19, 2016
γδ T cells has been shown to exhibit profound antitumor effects in a broad range of tumor entities, including OS. However, resistance to γδ T cells is a serious problem in the management of OS. This study investigates the impact of celastrol on the expression of death receptors 4/5 (DR4/5) on OS cell lines (HOS, U2OS) and cancer cell lysis by γδ T cells. The results showed that celastrol increased transcription of DR4/5 in HOS and U2OS, leading to increased cell surface, and total DR4/5 protein expression. Celastrol sensitizes OS cell lines or autologous OS cells to healthy donors-derived or OS patient-derived γδ T cell cytotoxicity in vitro. The induction of DR4/5 molecules increased lysis of HOS and U2OS by γδ T cells which was abolished by addition of a blocking TRAIL antibody. Importantly, the cytotoxic activity of γδ T cells was unaltered by small-dose celastrol. Taken together, our data show that celastrol up-regulated DR4/5 on OS cells to be responsible for intercellular TRAIL/APO-2L crosslink that confers increased cancer cell lysis by γδ T cells. These results suggest the clinical evaluation of celastrol in OS, especially in combination with immunotherapy approaches employing adoptive γδ T cell transfer.
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