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Abstract
Multiple myeloma (MM) is a fatal and incurable hematological malignancy thus new therapy need to be developed. Cold atmospheric plasma, a new technology that could generate various active species, could efficiently induce various tumor cells apoptosis. More details about the interaction of plasma and tumor cells need to be addressed before the application of gas plasma in clinical cancer treatment. In this study, we demonstrate that He+O2 plasma could efficiently induce myeloma cell apoptosis through the activation of CD95 and downstream caspase cascades. Extracellular and intracellular reactive oxygen species (ROS) accumulation is essential for CD95-mediated cell apoptosis in response to plasma treatment. Furthermore, p53 is shown to be a key transcription factor in activating CD95 and caspase cascades. More importantly, we demonstrate that CD95 expression is higher in tumor cells than in normal cells in both MM cell lines and MM clinical samples, which suggests that CD95 could be a favorable target for plasma treatment as it could selectively inactivate myeloma tumor cells. Our results illustrate the molecular details of plasma induced myeloma cell apoptosis and it shows that gas plasma could be a potential tool for myeloma therapy in the future.
Highlights
Multiple myeloma (MM), the second most common hematological malignancy characterized by the accumulation of malignant plasma cells (PCs) in the bone marrow (BM) of patients, results in the production of monoclonal immunoglobulin and substantial immune-suppression and end-organ www.oncotarget.com damage such as anemia, thrombocytopenia, renal failure, and bone disease [1]
We investigated whether CD95, a key death receptor that is pivotal for the induction of tumor cell apoptosis and is a major target in cancer therapy [11, 12], is involved in plasma induced cell apoptosis
By chromatin immune-precipitation (ChIP) assay, we demonstrated that p53, which was up-regulated by plasma treatment, could bind to the CD95 promoter region and increase CD95 expression, resulting in the activation of caspase signaling and induction of apoptosis
Summary
Multiple myeloma (MM), the second most common hematological malignancy characterized by the accumulation of malignant plasma cells (PCs) in the bone marrow (BM) of patients, results in the production of monoclonal immunoglobulin ( known as ‘M-protein’) and substantial immune-suppression and end-organ www.oncotarget.com damage such as anemia, thrombocytopenia, renal failure, and bone disease [1]. Radiation and several chemotherapy drugs can produce extracellular and intracellular ROS, disrupting redox homeostasis, which can induce tumor cell apoptosis [7, 8]. We investigated whether CD95, a key death receptor that is pivotal for the induction of tumor cell apoptosis and is a major target in cancer therapy [11, 12], is involved in plasma induced cell apoptosis. In addition to radio- and chemotherapies, a new technology called cold atmospheric plasma (CAP) could provide controllable exogenous reactive oxygen and nitrogen species [18, 19]. By chromatin immune-precipitation (ChIP) assay, we demonstrated that p53, which was up-regulated by plasma treatment, could bind to the CD95 promoter region and increase CD95 expression, resulting in the activation of caspase signaling and induction of apoptosis. Our results provide a new strategy for potential myeloma therapy by targeting CD95 with cold atmospheric plasma
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