Caffeine Inhibits Cell Proliferation and Regulates PKA/GSK3β Pathways in U87MG Human Glioma Cells

Ku, Bo Mi; Lee, Yeon Kyung; Jeong, Joo; Ryu, Jinhyun; Choi, Jungil; Kim, Joon Soo; Cho, Yong Woon; Roh, Gu Seob; Kim, Hyun Joon; Cho, Gyeong Jae; Choi, Wan Sung; Kang, Sang Soo

doi:10.1007/s10059-011-0027-5

Cited by 69 publications

(44 citation statements)

References 28 publications

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“…The nuclear localization of GSK-3β effects on the cell viability We also measured cell viability using FACS analysis to determine whether the subcellular localization of GSK-3β influenced the cell viability (Ku et al, 2011;Tanioka et al, 2011). As shown in Table 1, our FACS results indicate that the GSK-3β PY NLS mutants (R113A, Y117A) increased the cell survival rate significantly, compared to the HA-GSK-3β WT or K292R mutant which interacts with Kap β.…”

mentioning

confidence: 77%

The Nuclear Localization of Glycogen Synthase Kinase 3β Is Required Its Putative PY-Nuclear Localization Sequences

Sein

Lee

Chun

et al. 2012

Molecules and Cells

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Glycogen synthase kinase-3β(GSK-3β), which is a member of the serine/threonine kinase family, has been shown to be crucial for cellular survival, differentiation, and metabolism. Here, we present evidence that GSK-3β is associated with the karyopherin β2 (Kap β2) (102-kDa), which functions as a substrate for transportation into the nucleus. A potential PY-NLS motif ( 109 IVRLRYFFY 117) was observed, which is similar with the consensus PY NLS motif (R/K/H)X 2-5 PY in the GSK-3β catalytic domain. Using a pull down approach, we observed that GSK-3β physically interacts with Kap β2 both in vivo and in vitro. Secondly, GSK-3β and Kap β2 were shown to be co-localized by confocal microscopy. The localization of GSK-3β to the nuclear region was disrupted by putative Kap β2 binding site mutation. Furthermore, in transient transfection assays, the Kap β2 binding site mutant induced a substantial reduction in the in vivo serine/threonine phosphorylation of GSK-3β, where-as the GSK-3β wild type did not. Thus, our observations indicated that Kap β2 imports GSK-3β through its putative PY NLS motif from the cytoplasm to the nucleus and increases its kinase activity.

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mentioning

confidence: 77%

The Nuclear Localization of Glycogen Synthase Kinase 3β Is Required Its Putative PY-Nuclear Localization Sequences

Sein

Lee

Chun

et al. 2012

Molecules and Cells

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“…Moreover, caffeine can suppress glioma cell proliferation by modulating cell cycle checkpoints and perturbing key cell cycle regulatory proteins [9]. Although caffeine can increase apoptosis of glioma cells [10], the exact mechanism of caffeine-induced apoptosis remains unclear [11].…”

Section: Introductionmentioning

confidence: 99%

Caffeine-induced nuclear translocation of FoxO1 triggers Bim-mediated apoptosis in human glioblastoma cells

et al. 2015

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Caffeine is one of the most commonly ingested neuroactive compounds and exhibits anticancer effects through induction of apoptosis and suppression of cell proliferation. However, the mechanisms underlying these effects are currently unknown. In this study, we investigated the mechanisms of caffeine-induced apoptosis in U251 cells (human glioma cell line). We analyzed the inhibitory effects of caffeine on cell proliferation by performing WST-8 and colony formation assays; in addition, cell survival was assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and flow cytometric analysis. Western blotting was used to investigate the role played by FoxO1 in the proapoptotic effects of caffeine on glioma cells. Results showed that caffeine inhibited proliferation and survival of human glioma cells, induced apoptosis, and increased the expression of FoxO1 and its proapoptotic target Bim. In addition, we found that FoxO1 enhanced the transcription of its proapoptotic target Bim. In summary, our data indicates that FoxO1-Bim mediates caffeine-induced regression of glioma growth by activating cell apoptosis, thereby providing new mechanistic insight into the possible use of caffeine in treating human cancer.

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“…CT99021 at 1 mM was shown to reduce GSK3b activity to 1% in an in vitro assay in which the inhibitor was shown to be highly specific [32]. H-89 at 10 mM was used to activate GSK3, as it is a robust activator of GSK3 whose inclusion in culture medium has been shown to prevent or inhibit the phosphorylation of GSK3 (which would inactivate GSK3) in embryonic kidney cells at 10 mM [31,50], muscle cells at 50 mM [51], spermatozoa at 100 mM [52], and glioma cells at 10 mM [53]. Pifithrin-a was used to inhibit p53 at 30 mM [38], as it has been established as an effective inhibitor of p53 that blocks the activation of p53 responsive LacZ in ConA cells, and inhibits p53-mediated apoptosis at 10-20 mM [54].…”

Section: Insulin and Inhibitorsmentioning

confidence: 99%

Insulin Increases Epiblast Cell Number of In Vitro Cultured Mouse Embryos via the PI3K/GSK3/p53 Pathway

Campbell

Nottle

Vassiliev

et al. 2012

Stem Cells and Development

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Authors may also deposit this version on his/her funder's or funder's designated repository at the funder's request or as a result of a legal obligation, provided it is not made publicly available until 12 months after official publication. th March 2013Insulin High-quality embryos give rise to embryonic stem cells (ESCs) at greater efficiencies than poor-quality embryos. However, most embryos available for human ESC derivation are of a reduced quality as a result of culture in relatively simple media up to 10 years earlier, before cryopreservation, or before compaction. In the present study, we used a mouse model to determine whether a culture with insulin from the 8-cell stage could increase the number of ESC progenitor epiblast cells in blastocysts, as well as endeavor to determine the molecular mechanism of the insulin's effect. Culture in media containing 1.7 rM insulin increased epiblast cell number (determined by Oct4 and Nanog co-expression), and proportion in day 6 blastocysts. The inhibition of phosphoinositide 3 kinase (PI3K) (via LY294002), an early second messenger of the insulin receptor, blocked this effect. The inhibition of glycogen synthase kinase 3 (GSK3) or p53, 2 s messengers inactivated by insulin signaling (via CT99021 or pifithrin-a, respectively), increased epiblast cell numbers. When active, GSK3 and p53 block the transcription of Nanog, which is important for maintaining pluripotency. A simultaneous inhibition of GSK3 and p53 had no synergistic effects on epiblast cell number. The induced activation of GSK3 and p53, via the inhibition of proteins responsible for their inactivation (PKA via H-89 and SIRT-1 via nicotinamide, respectively), blocked the insulin's effect on the epiblast.From our findings, we conclude that insulin increases epiblast cell number via the activation of PI3K, which ultimately inactivates GSK3 and p53. Furthermore, we suggest that the inclusion of insulin in culture media could be used as a strategy for increasing the efficiency with which the ESC lines can be derived from cultured embryos.

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Caffeine Inhibits Cell Proliferation and Regulates PKA/GSK3β Pathways in U87MG Human Glioma Cells

Cited by 69 publications

References 28 publications

The Nuclear Localization of Glycogen Synthase Kinase 3β Is Required Its Putative PY-Nuclear Localization Sequences

The Nuclear Localization of Glycogen Synthase Kinase 3β Is Required Its Putative PY-Nuclear Localization Sequences

Caffeine-induced nuclear translocation of FoxO1 triggers Bim-mediated apoptosis in human glioblastoma cells

Insulin Increases Epiblast Cell Number of In Vitro Cultured Mouse Embryos via the PI3K/GSK3/p53 Pathway

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