title: Metformin increases sensitivity of osteosarcoma stem cells to cisplatin by inhibiting expression of PKM2.
abstract: Multiple drug resistance is reported to be a major obstacle in treatment of osteosarcoma (OS). Research has demonstrated that small subsets of cells called cancer stem cells (CSCs) are responsible for multiple drug resistance. CSCs are potential targets for reversing chemoresistance. In the present study, we compared cisplatin sensitivity between OS stem cells and OS non-stem cells. We confirmed that OS stem cells showed significant cisplatin-resistance compared with the OS non-CSCs. Mechanically, we proved that overexpression of the pyruvate kinase isoenzyme M2 (PKM2) was responsible for the resistance to cisplatin in OS stem cells. As a potential strategy, we found that co-treatment with metformin significantly decreased the half maximal inhibitory concentration (IC50) of cisplatin to HOS OS stem cells by downregulating the expression of PKM2. PKM2 downregulation resulted in, metformin inhibited glucose uptake, lactate production and ATP production in HOS CSCs. Therefore, metformin impaired the resistance of HOS CSCs to cisplatin and promoted cisplatin-induced apoptosis. In addition, antitumor effects of other chemotherapeutic drugs such as doxorubicin and 5-fluorouracil were proved to be enhanced by metformin on OS stem cells.
authors.affiliation: Department of Orthopedics, Zhongshan Hospital Affiliated of Dalian University, Dalian, Liaoning 116001, P.R. China.
authors.forename: Depeng
authors.initials: D
authors.lastname: Shang
authors.affiliation: Department of General Surgery, Zhongshan Hospital Affiliated of Dalian University, Dalian, Liaoning 116001, P.R. China.
authors.forename: Ju
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning 121001, P.R. China.
authors.forename: Lianyi
authors.initials: L
authors.lastname: Guo
authors.affiliation: Department of Orthopedics, Zhongshan Hospital Affiliated of Dalian University, Dalian, Liaoning 116001, P.R. China.
authors.forename: Yanju
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Orthopedics, Zhongshan Hospital Affiliated of Dalian University, Dalian, Liaoning 116001, P.R. China.
authors.forename: Lezi
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Orthopedics, Zhongshan Hospital Affiliated of Dalian University, Dalian, Liaoning 116001, P.R. China.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Lu
mesh_terms: D000255:Adenosine Triphosphate; D017209:Apoptosis / Q000187:drug effects; D002352:Carrier Proteins / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis*; D008687:Metformin / Q000008:administration & dosage*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D012516:Osteosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D013963:Thyroid Hormones / Q000096:biosynthesis*; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D000255:Adenosine Triphosphate; D002352:Carrier Proteins; D002945:Cisplatin; D004317:Doxorubicin; D005947:Glucose; D008565:Membrane Proteins; D008687:Metformin; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins