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

Saiki, Sachio; Sasazawa, Yukiko; Imamichi, Yoko; Kawajiri, Sumihiro; Fujimaki, Takahiro; Tanida, Isei; Kobayashi, Hiroki; Sato, Fumiaki; Sato, Shigeto; Ishikawa, Keiichi; Imoto, Masaya; Hattori, Nobutaka

doi:10.4161/auto.7.2.14074

Cited by 379 publications

(315 citation statements)

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“…2A). Contradicting the role of ATM as a positive regulator of autophagy, caffeine was recently shown to induce autophagy in mammalian cells (29). In line with this, caffeine induced autophagic flux in MCF7 cells at 4 mM and enhanced rapamycin-induced autophagic flux at 0.5 and 1 mM (Fig.…”

Section: Identification Of Small Molecule Inhibitors Of Autophagy-supporting

confidence: 59%

“…This aspect is particularly challenging within the autophagy field since the family in addition to ATM and PtdIns(3)K includes the notorious autophagy inhibitors mTor and class I PI3Ks. The lack of specificity may also explain the paradoxical effects of caffeine observed herein where low and high concentrations promote and inhibit autophagy respectively, probably reflecting different thresholds for inhibition of the Akt/mTor/p70S6 pathway and PtdIns3K (29).…”

Section: Discussionmentioning

confidence: 87%

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Identification of Small Molecule Inhibitors of Phosphatidylinositol 3-Kinase and Autophagy

Farkas

Daugaard

Jäättelä

2011

Journal of Biological Chemistry

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Macroautophagy (hereafter autophagy) is a lysosomal catabolic pathway that controls cellular homeostasis and survival. It has recently emerged as an attractive target for the treatment of a variety of degenerative diseases and cancer. The targeting of autophagy has, however, been hampered by the lack of specific small molecule inhibitors. Thus, we screened two small molecule kinase inhibitor libraries for inhibitors of rapamycin-induced autophagic flux. The three most potent inhibitors identified conferred profound inhibition of autophagic flux by inhibiting the formation of autophagosomes. Notably, the autophagy inhibitory effects of all three compounds were independent of their established kinase targets, i.e. ataxia telangiectasia mutated for KU55933, protein kinase C for Gö6976, and Janus kinase 3 for Jak3 inhibitor VI. Instead, we identified phosphatidylinositol 3-kinase (PtdIns3K) as a direct target of KU55933 and Gö6976. Importantly, and in contrast to the currently available inhibitors of autophagosome formation (e.g. 3-methyladenine), none of the three compounds inhibited the cell survival promoting class I phosphoinositide 3-kinase-Akt signaling at the concentrations required for effective autophagy inhibition. Accordingly, they proved to be valuable tools for investigations of autophagy-associated cell death and survival. Employing KU55399, we demonstrated that autophagy protects amino acid-starved cells against both apoptosis and necroptosis. Taken together, our data introduce new possibilities for the experimental study of autophagy and can form a basis for the development of clinically relevant autophagy inhibitors.Autophagy is an intracellular degradative process by which cells recycle macromolecules and organelles (1-4). In this process, cellular material is sequestered in double membrane vesicles termed autophagosomes that fuse with lysosomes to form autolysosomes, in which the cargo is exposed to acidic hydrolases. Autophagy is essential for energy homeostasis and removal of damaged organelles and protein complexes during various kinds of stresses, such as starvation, growth factor deprivation, hypoxia, and DNA damage. It is also involved in physiological processes like development, immunity, and aging as well as in various diseases including neurodegenerative disorders and cancer. Whereas autophagy clearly has a beneficial effect in preventing many degenerative disorders, its role in cancer is more complex. It can function as a tumor suppressor mechanism, and yet it can also promote tumor growth by protecting cancer cells against the hostile tumor environment and antineoplastic drugs (5, 6).The mammalian target of rapamycin complex 1 (mTORC1) 3 serine/threonine kinase integrates information on cell metabolic, growth, and stress status to regulate biosynthetic pathways and autophagy (7,8). It activates biosynthetic pathways and inhibits autophagy in response to various growth factors via MAPK/ERK and class I phosphoinositide 3-kinase (PI3K)/Aktdependent pathways. On the other hand, when the ene...

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Section: Identification Of Small Molecule Inhibitors Of Autophagy-supporting

confidence: 59%

Section: Discussionmentioning

confidence: 87%

Identification of Small Molecule Inhibitors of Phosphatidylinositol 3-Kinase and Autophagy

Farkas

Daugaard

Jäättelä

2011

Journal of Biological Chemistry

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“…mTOR serves as a negative regulator of autophagy activation 14. As shown in Figure 3, the levels of p‐mTOR were decreased by tetracaine (67.9%), bupivacaine (73.8%), ropivacaine (50.8%), procaine (71.6%) and lidocaine (67.5%), respectively, compared with the untreated controls ( P < 0.01).…”

Section: Resultsmentioning

confidence: 85%

Autophagy activated by tuberin/mTOR/p70S6K suppression is a protective mechanism against local anaesthetics neurotoxicity

Xiong

Kong

Dai

et al. 2016

J Cellular Molecular Medi

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The local anaesthetics (LAs) are widely used for peripheral nerve blocks, epidural anaesthesia, spinal anaesthesia and pain management. However, exposure to LAs for long duration or at high dosage can provoke potential neuronal damages. Autophagy is an intracellular bulk degradation process for proteins and organelles. However, both the effects of LAs on autophagy in neuronal cells and the effects of autophagy on LAs neurotoxicity are not clear. To answer these questions, both lipid LAs (procaine and tetracaine) and amide LAs (bupivacaine, lidocaine and ropivacaine) were administrated to human neuroblastoma SH‐SY5Y cells. Neurotoxicity was evaluated by MTT assay, morphological alterations and median death dosage. Autophagic flux was estimated by autolysosome formation (dual fluorescence LC3 assay), LC3‐II generation and p62 protein degradation (immunoblotting). Signalling alterations were examined by immunoblotting analysis. Inhibition of autophagy was achieved by transfection with beclin‐1 siRNA. We observed that LAs decreased cell viability in a dose‐dependent manner. The neurotoxicity of LAs was tetracaine > bupivacaine > ropivacaine > procaine > lidocaine. LAs increased autophagic flux, as reflected by increases in autolysosome formation and LC3‐II generation, and decrease in p62 levels. Moreover, LAs inhibited tuberin/mTOR/p70S6K signalling, a negative regulator of autophagy activation. Most importantly, autophagy inhibition by beclin‐1 knockdown exacerbated the LAs‐provoked cell damage. Our data suggest that autophagic flux was up‐regulated by LAs through inhibition of tuberin/mTOR/p70S6K signalling, and autophagy activation served as a protective mechanism against LAs neurotoxicity. Therefore, autophagy manipulation could be an alternative therapeutic intervention to prevent LAs‐induced neuronal damage.

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“…As a point of interest, a growing number of studies show that p70S6K survival signaling is a key antiapoptotic factor, by various pathways. From a molecular point of view, autophagy induction, decreased oxidative stress, and inactivation of proapoptotic molecules, such as Bcl-2-associated death promoter, are commonly described downstream of p70S6K signaling (Faghiri and Bazan 2010;Saiki et al 2011;Harada et al 2001).…”

Section: Discussionmentioning

confidence: 99%

Collaboration of geldanamycin-activated P70S6K and Hsp70 against beta-amyloid-induced hippocampal apoptosis: an approach to long-term memory and learning

Zare

Motamedi

Digaleh

et al. 2015

Cell Stress and Chaperones

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One of the neuropathological hallmarks of Alzheimer's disease (AD) is the accumulation of betaamyloid peptides (Aβ) in senile plaques. Aβ-induced oxidative stress is believed to be responsible for degeneration and apoptosis of neurons and consequent cognitive and memory deficits. Here, we investigated the possible neuroprotective effect of the heat shock protein 90 (Hsp90) inhibitor geldanamycin (GA) against amyloid pathogenesis in adult male Wistar rats. GA or vehicle was injected into the lateral cerebral ventricles of rats 24 h before injection of Aβ (1-42) in CA1 area of hippocampus. The learning and memory of the rats were assessed 7 days after injection of Aβ using passive avoidance (PA) task. As potential contributing factors in Aβ-induced memory decline, we evaluated apoptotic markers and also used terminal-transferase UTP nick end labeling (TUNEL) technique to detect apoptosis in the hippocampus of Aβ-injected rats. Our behavioral data suggest that GA pretreatment can significantly suppress memory deficits in Aβ-injected rats. There was also not only a marked increase in Hsp70 level but also upregulated 70 kDa ribosomal protein S6 kinase (p70S6K) in the hippocampus of GA-treated groups with a reduction in apoptotic factors including caspase-3, poly (ADP-ribose) polymerase, Bax/Bcl-2 ratio, and TUNELpositive cells as well. Thus, we conclude that GA exerts its protective effects against Aβ (1-42) toxicity and memory deficits, at least in part, by upregulating of Hsp70 and P70S6K.

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

Cited by 379 publications

References 43 publications

Identification of Small Molecule Inhibitors of Phosphatidylinositol 3-Kinase and Autophagy

Identification of Small Molecule Inhibitors of Phosphatidylinositol 3-Kinase and Autophagy

Autophagy activated by tuberin/mTOR/p70S6K suppression is a protective mechanism against local anaesthetics neurotoxicity

Collaboration of geldanamycin-activated P70S6K and Hsp70 against beta-amyloid-induced hippocampal apoptosis: an approach to long-term memory and learning

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