title: Celastrol increases osteosarcoma cell lysis by γδ T cells through up-regulation of death receptors.
abstract: 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.
authors: Department of Orthopaedics, Affiliated Hospital, Guilin Medical University, Guilin, Guangxi, China.
authors: Zhaoxu
authors: Z
authors: Li
authors: Department of Orthopaedics, Affiliated Hospital, Guilin Medical University, Guilin, Guangxi, China.
authors: Junzhe
authors: J
authors: Zhang
authors: Department of Orthopaedics, Affiliated Hospital, Guilin Medical University, Guilin, Guangxi, China.
authors: Jicun
authors: J
authors: Tang
authors: Department of Orthopaedics, Affiliated Hospital, Guilin Medical University, Guilin, Guangxi, China.
authors: Ruiying
authors: R
authors: Wang
mesh_terms: D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic / Q000187:drug effects* / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D012516:Osteosarcoma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053978:Pentacyclic Triterpenes; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology / Q000378:metabolism; D053218:Receptors, Death Domain / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D053978:Pentacyclic Triterpenes; D016692:Receptors, Antigen, T-Cell, gamma-delta; D053218:Receptors, Death Domain; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; D014315:Triterpenes; C050414:celastrol
keywords: TNF-related apoptosis-inducing ligand; immunotherapy; osteosarcoma; tripterine