Molecular mechanisms of hyperthermia-induced apoptosis enhanced by docosahexaenoic acid: Implication for cancer therapy

• Published in: Chemico-biological interactions 2014-05, Vol.215, p.46-53
• Main Authors: Cui, Zheng-Guo, Piao, Jin-Lan, Kondo, Takashi, Ogawa, Ryohei, Tsuneyama, Koichi, Zhao, Qing-Li, Feril, Loreto B., Inadera, Hidekuni
• Format: Article
• Language: English
• Subjects: Apoptosis; Apoptosis - drug effects; Cancer; Cell Line, Tumor; Docosahexaenoic acid; Docosahexaenoic Acids - pharmacology; Docosahexaenoic Acids - therapeutic use; Gene Expression Regulation, Neoplastic - drug effects; Humans; Hyperthermia; Hyperthermia, Induced; Intracellular Space - drug effects; Intracellular Space - metabolism; Mitochondria - metabolism; Mitogen-Activated Protein Kinases - metabolism; PKC-δ; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-bcl-2 - metabolism; Reactive Oxygen Species - metabolism
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/j.cbi.2014.03.005

•Hyperthermia-induced apoptosis was significantly enhanced by DHA.•DHA synergizes hyperthermia to induce excess intracellular oxidative stress.•Activation of PKC-δ plays important role in the enhancement of apoptosis. 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.