Caffeine induces apoptosis by enhancement of autophagy via PI3K/Akt/mTOR/p70S6K inhibition

Shinji Saiki, Yukiko Sasazawa, Yoko Imamichi, Sumihiro Kawajiri, Takahiro Fujimaki, Isei Tanida, Hiroki Kobayashi, Fumiaki Sato, Shigeto Sato, Kei Ichi Ishikawa, Masaya Imoto, Nobutaka Hattori

Research output: Contribution to journalArticle

242 Citations (Scopus)

Abstract

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 in 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.

Original languageEnglish
Pages (from-to)176-187
Number of pages12
JournalAutophagy
Volume7
Issue number2
DOIs
Publication statusPublished - 2011 Feb

Fingerprint

70-kDa Ribosomal Protein S6 Kinases
Autophagy
Caffeine
Phosphatidylinositol 3-Kinases
Apoptosis
Ribosomal Protein S6
Insulin
Ribosomal Protein S6 Kinases
Microtubule-Associated Proteins
MAP Kinase Signaling System
Propidium
Mitochondrial Membrane Potential
Annexin A5
Small Interfering RNA
Electron Microscopy
Cell Cycle
Cell Death
Therapeutics
Fibroblasts
Western Blotting

Keywords

  • Apoptosis
  • Autophagy
  • Caffeine
  • ERK1/2
  • PI3K/Akt/mTOR/p70S6K

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Saiki, S., Sasazawa, Y., Imamichi, Y., Kawajiri, S., Fujimaki, T., Tanida, I., ... Hattori, N. (2011). Caffeine induces apoptosis by enhancement of autophagy via PI3K/Akt/mTOR/p70S6K inhibition. Autophagy, 7(2), 176-187. https://doi.org/10.4161/auto.7.2.14074

Caffeine induces apoptosis by enhancement of autophagy via PI3K/Akt/mTOR/p70S6K inhibition. / Saiki, Shinji; Sasazawa, Yukiko; Imamichi, Yoko; Kawajiri, Sumihiro; Fujimaki, Takahiro; Tanida, Isei; Kobayashi, Hiroki; Sato, Fumiaki; Sato, Shigeto; Ishikawa, Kei Ichi; Imoto, Masaya; Hattori, Nobutaka.

In: Autophagy, Vol. 7, No. 2, 02.2011, p. 176-187.

Research output: Contribution to journalArticle

Saiki, S, Sasazawa, Y, Imamichi, Y, Kawajiri, S, Fujimaki, T, Tanida, I, Kobayashi, H, Sato, F, Sato, S, Ishikawa, KI, Imoto, M & Hattori, N 2011, 'Caffeine induces apoptosis by enhancement of autophagy via PI3K/Akt/mTOR/p70S6K inhibition', Autophagy, vol. 7, no. 2, pp. 176-187. https://doi.org/10.4161/auto.7.2.14074
Saiki S, Sasazawa Y, Imamichi Y, Kawajiri S, Fujimaki T, Tanida I et al. Caffeine induces apoptosis by enhancement of autophagy via PI3K/Akt/mTOR/p70S6K inhibition. Autophagy. 2011 Feb;7(2):176-187. https://doi.org/10.4161/auto.7.2.14074
Saiki, Shinji ; Sasazawa, Yukiko ; Imamichi, Yoko ; Kawajiri, Sumihiro ; Fujimaki, Takahiro ; Tanida, Isei ; Kobayashi, Hiroki ; Sato, Fumiaki ; Sato, Shigeto ; Ishikawa, Kei Ichi ; Imoto, Masaya ; Hattori, Nobutaka. / Caffeine induces apoptosis by enhancement of autophagy via PI3K/Akt/mTOR/p70S6K inhibition. In: Autophagy. 2011 ; Vol. 7, No. 2. pp. 176-187.
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