カワジリ　スミヒロ   KAWAJIRI Sumihiro   河尻　澄宏    所属   医学部 医学科（附属東洋医学研究所）    職種   准教授
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	Caffeine induces apoptosis by enhancement of autophagy via PI3K/Akt/mTOR/p70S6K inhibition.
掲載誌名	正式名：Autophagy 略　 称：Autophagy ISSNコード：15548635/15548627
掲載区分	国外
巻・号・頁	7(2),pp.176-87
著者・共著者	Saiki Shinji, Sasazawa Yukiko, Imamichi Yoko, Kawajiri Sumihiro, Fujimaki Takahiro, Tanida Isei, Kobayashi Hiroki, Sato Fumiaki, Sato Shigeto, Ishikawa Ken-Ichi, Imoto Masaya, Hattori Nobutaka
発行年月	2011/02
概要	Caffeine is one of the most frequently ingested neuroactive compounds. All known mechanisms of apoptosis induced by caffeine act through cell cycle modulation or p53 induction. It is currently unknown whether caffeine-induced apoptosis is associated with other cell death mechanisms, such as autophagy. Herein we show that caffeine increases both the levels of microtubule-associated protein 1 light chain 3-II and the number of autophagosomes, through the use of western blotting, electron microscopy and immunocytochemistry techniques. Phosphorylated p70 ribosomal protein S6 kinase (Thr389), S6 ribosomal protein (Ser235/236), 4E-BP1 (Thr37/46) and Akt (Ser473) were significantly decreased by caffeine. In contrast, ERK1/2 (Thr202/204) was increased by caffeine, suggesting an inhibition of the Akt/mTOR/p70S6K pathway and activation of the ERK1/2 pathway. Although insulin treatment phosphorylated Akt (Ser473) and led to autophagy suppression, the effect of insulin treatment was completely abolished by caffeine addition. Caffeine-induced autophagy was not completely blocked by inhibition of ERK1/2 by U0126. Caffeine induced reduction of mitochondrial membrane potentials and apoptosis in a dose-dependent manner, which was further attenuated by the inhibition of autophagy with 3-methyladenine or Atg7 siRNA knockdown. Furthermore, there was a reduced number of early apoptotic cells (annexin V positive, propidium iodide negative) among autophagy-deficient mouse embryonic fibroblasts treated with caffeine than their wild-type counterparts. These results support previous studies on the use of caffeine in the treatment of human tumors and indicate a potential new target in the regulation of apoptosis.
DOI	10.4161/auto.7.2.14074
PMID	21081844