title: TRAIL restores DCA/metformin-mediated cell death in hypoxia.
abstract: Previous studies have shown that hypoxia can reverse DCA/metformin-induced cell death in breast cancer cells. Therefore, targeting hypoxia is necessary for therapies targeting cancer metabolism. In the present study, we found that TRAIL can overcome the effect of hypoxia on the cell death induced by treatment of DCA and metformin in breast cancer cells. Unexpectedly, DR5 is upregulated in the cells treated with DCA/metformin, and sustained under hypoxia. Blocking DR5 by siRNA inhibited DCA/metformin/TRAIL-induced cell death, indicating that DR5 upregulation plays an important role in sensitizing cancer cells to TRAIL-induced cell death. Furthermore, we found that activation of JNK and c-Jun is responsible for upregulation of DR5 induced by DCA/metformin. These findings support the potential application of combining TRAIL and metabolism-targeting drugs in the treatment of cancers under hypoxia.
authors: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul 01812, Republic of Korea; Department of Food and Microbial Technology, Seoul Women's University, 621 Hwarangro, Nowon-gu, Seoul 01797, Republic of Korea.
authors: Sung-Eun
authors: SE
authors: Hong
authors: Department of Microbiological Engineering, Kon-Kuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea.
authors: Chang Soon
authors: CS
authors: Kim
authors: Department of Microbiological Engineering, Kon-Kuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea.
authors: Sungkwan
authors: S
authors: An
authors: Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological & Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul 01812, Republic of Korea.
authors: Hyun-Ah
authors: HA
authors: Kim
authors: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul 01812, Republic of Korea.
authors: Sang-Gu
authors: SG
authors: Hwang
authors: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul 01812, Republic of Korea.
authors: Jie-Young
authors: JY
authors: Song
authors: KIRAMS Radiation Biobank, Korea Institute of Radiological & Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul 01812, Republic of Korea.
authors: Jin Kyung
authors: JK
authors: Lee
authors: Department of Food and Microbial Technology, Seoul Women's University, 621 Hwarangro, Nowon-gu, Seoul 01797, Republic of Korea.
authors: Jungil
authors: J
authors: Hong
authors: Department of Food and Microbial Technology, Seoul Women's University, 621 Hwarangro, Nowon-gu, Seoul 01797, Republic of Korea.
authors: Jong-Il
authors: JI
authors: Kim
authors: Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological & Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul 01812, Republic of Korea.
authors: Woo Chul
authors: WC
authors: Noh
authors: KIRAMS Radiation Biobank, Korea Institute of Radiological & Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul 01812, Republic of Korea. Electronic address: hyeonok@kirams.re.kr.
authors: Hyeon-Ok
authors: HO
authors: Jin
authors: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul 01812, Republic of Korea. Electronic address: parkic@kirams.re.kr.
authors: In-Chul
authors: IC
authors: Park
mesh_terms: D001943:Breast Neoplasms / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D061986:MCF-7 Cells; D008687:Metformin / Q000494:pharmacology*; D053218:Receptors, Death Domain / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D053218:Receptors, Death Domain; D053221:TNF-Related Apoptosis-Inducing Ligand; D008687:Metformin; D003999:Dichloroacetic Acid; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Cancer metabolism; Dichloroacetate; Hypoxia; Metformin; TRAIL