title: Molecular mechanisms of hyperthermia-induced apoptosis enhanced by docosahexaenoic acid: implication for cancer therapy.
abstract: To develop a non-toxic enhancer for hyperthermia-induced cell death as a potential cancer treatment, we studied the effect and mechanism of docosahexaenoic acid (DHA) on hyperthermia-induced apoptosis. Treatment with 20μM DHA and 44°C for 10min induced significant apoptosis, increased intracellular reactive oxygen species (ROS), and caspase-3 activation in U937 cells, but heat or DHA alone did not induce notable apoptosis. Decreased mitochondrial transmembrane potentials were dramatically increased by the combined treatment, accompanied by increased pro-apoptotic Bcl-2 family protein tBid, and decreased anti-apoptotic Bcl-2 and Bcl-xL. Combined hyperthermia-DHA treatment induced significant phosphorylation of protein kinase C (PKC)-δ (p-PKC-δ), and apoptosis in a DHA dose-dependent manner. Using both 20μM DHA and 44°C for 10min induced significant PKC-δ cleavage and its translocation to mitochondria. These results were also seen in HeLa cells. However, MAPKs and Akt were not affected by the treatment. In conclusion, DHA enhances hyperthermia-induced apoptosis significantly via a mitochondria-caspase-dependent pathway; its underlying mechanism involves elevated intracellular ROS, mitochondria dysfunction, and PKC-δ activation.
authors.affiliation: Department of Public Health, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama-city, Toyama 930-0194, Japan. Electronic address: sai@med.u-toyama.ac.jp.
authors.forename: Zheng-Guo
authors.initials: ZG
authors.lastname: Cui
authors.affiliation: Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama-city, Toyama 930-0194, Japan. Electronic address: d1061016@ems.u-toyama.ac.jp.
authors.forename: Jin-Lan
authors.initials: JL
authors.lastname: Piao
authors.affiliation: Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama-city, Toyama 930-0194, Japan. Electronic address: kondot@med.u-toyama.ac.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kondo
authors.affiliation: Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama-city, Toyama 930-0194, Japan. Electronic address: ogawa@med.u-toyama.ac.jp.
authors.forename: Ryohei
authors.initials: R
authors.lastname: Ogawa
authors.affiliation: Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama-city, Toyama 930-0194, Japan. Electronic address: ktsune@med.u-toyama.ac.jp.
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.affiliation: Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama-city, Toyama 930-0194, Japan. Electronic address: zhao@med.u-toyama.ac.jp.
authors.forename: Qing-Li
authors.initials: QL
authors.lastname: Zhao
authors.affiliation: Department of Anatomy, Fukuoka University School of Medicine, Nanakuma 7-45-1, Fukuoka 814-0180, Japan. Electronic address: feril@fukuoka-u.ac.jp.
authors.forename: Loreto B
authors.initials: LB
authors.lastname: Feril
authors.affiliation: Department of Public Health, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama-city, Toyama 930-0194, Japan. Electronic address: inadera@med.u-toyama.ac.jp.
authors.forename: Hidekuni
authors.initials: H
authors.lastname: Inadera
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004281:Docosahexaenoic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006979:Hyperthermia, Induced; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D004281:Docosahexaenoic Acids; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases
keywords: Apoptosis; Cancer; Docosahexaenoic acid; Hyperthermia; PKC-δ