title: PGC-1α is responsible for survival of multiple myeloma cells under hyperglycemia and chemotherapy.
abstract: The association between hyperglycemia and outcomes during chemotherapy has been reported in several tumors, including multiple myeloma (MM). However, the underlying mechanism of how hyperglycemia affects the survival of MM cells during chemotherapy remain to be elucidated. MM cells were cultured in 10 mM glucose with or without chemotherapeutic agents. Following treatment of MM cells with dexamethasone or bortezomib, an MTT assay was used to evaluate the toxicity of dexamethasone or bortezomib on cell proliferation, and changes of reactive oxygen species (ROS) level were detected by flow cytometry (FCM) analysis. Small interference RNA (siRNA) was applied to inhibit the expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α). Expressions of PGC-1α and antioxidant factors such as superoxide dismutase 2 (SOD‑2), glutathione peroxidase 1 (GPX-1), and catalase (CAT) were measured by RT-PCR prior to and following treatment. The results showed that the level of PGC-1α in MM cells cultured in high-glucose medium was upregulated prior to and following treatment of chemotherapeutic agents, and these cells showed less fold-change of ROS after insult of drugs, when compared to the control. Genes encoding antioxidant factors such as SOD-2 and CAT were also upregulated. Inhibition of PGC-1α enhanced the toxicity of antitumor agents, associated with reduced expression of antioxidant factors, and elevated level of ROS. The present findings suggested that hyperglycemia may influence the anticancer effect of chemotherapeutic agents in MM by upregulating the expression of PGC-1α and associated antioxidant factors. Inhibition of PGC-1α or control of hyperglycemia may be beneficial in improving the efficacy of chemotherapy in MM patients with diabetes.
authors.affiliation: Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430000, P.R. China.
authors.forename: Wen
authors.initials: W
authors.lastname: Yu
authors.affiliation: Institute of Cancer, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei 430000, P.R. China.
authors.forename: Dedong
authors.initials: D
authors.lastname: Cao
authors.affiliation: Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430000, P.R. China.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430000, P.R. China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430000, P.R. China.
authors.forename: Tao
authors.initials: T
authors.lastname: Guo
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D000975:Antioxidants / Q000378:metabolism; D002374:Catalase / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics*; D005947:Glucose / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000235:genetics; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics*; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D000094765:Glutathione Peroxidase GPX1; D000099156:Superoxide Dismutase 2
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D002374:Catalase; D005947:Glucose; D005979:Glutathione Peroxidase; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D014157:Transcription Factors; D000094765:Glutathione Peroxidase GPX1; D000099156:Superoxide Dismutase 2; C486497:PPARGC1A protein, human; C000722067:GPX1 protein, human