Phosphoinositide 3-kinase accelerates autophagic cell death during glucose deprivation in the rat cardiomyocyte-derived cell line H9c2

Aki, Toshihiko; Yamaguchi, Kazuhito; Fujimiya, Tatsuya; Mizukami, Yoichi

doi:10.1038/sj.onc.1207197

Cited by 118 publications

(102 citation statements)

References 27 publications

(26 reference statements)

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“…In another study, insulin-like growth factor-1 and the adenovirusmediated overexpression of wild-type class I PIK3CA accelerates the accumulation of autophagic vacuoles and subsequent autophagic cell death during glucose deprivation. 37 From this point of view, abnormally activated AKT signaling pathway by other than loss of PTEN in the current study could possibly change its downstream targets and result in the opposite outcome, or AKT1 might show a different action specifically in intrahepatic cholangiocarcinomas.…”

Section: Discussionmentioning

confidence: 72%

The expression of phospho-AKT1 and phospho-MTOR is associated with a favorable prognosis independent of PTEN expression in intrahepatic cholangiocarcinomas

Lee

Choi

et al. 2012

Modern Pathology

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AKT1 signaling pathway is important for the regulation of protein synthesis and cell survival with implications in carcinogenesis. In this study, we explored the prognostic significance of AKT1 pathway in intrahepatic cholangiocarcinomas. We investigated the status of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), phosphorylated (p) AKT1 (p-AKT1), p-mammalian target of rapamycin (p-MTOR), p-p70 ribosomal protein S6 kinase (p-RPS6KB2) and p-eukaryotic initiation factor 4E-binding protein-1 (p-EIF4EBP1) in 101 intrahepatic cholangiocarcinomas by immunohistochemistry. Western blot analysis was performed to verify the expression levels of p-AKT1 and p-MTOR. The relationship of protein expression with clinicopathological data and the correlations of protein expression levels were explored. The overexpression of p-AKT1, p-MTOR, and PTEN was associated with a better survival in patients with intrahepatic cholangiocarcinoma (P ¼ 0.0137, 0.0194, and 0.0337, respectively). In a multivariate analysis, PTEN was an independent prognostic factor, and p-AKT1 showed tendency (P ¼ 0.032 and 0.051, respectively). The overexpression of p-MTOR was correlated with well-to-moderately differentiated tumors (Po0.001) and tumors without metastasis (P ¼ 0.046). Expression levels of the AKT1 signaling pathway proteins in this study showed positive correlations with each other, except for PTEN. Aberrant expressions of p-AKT1 and p-MTOR in intrahepatic cholangiocarcinoma were associated with a favorable prognosis, possibly in a PTEN-independent manner. Our results indicate that dysregulation of the AKT1 pathway may have an important role in the development of intrahepatic cholangiocarcinoma, but not necessarily in the progression of the disease.

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Section: Discussionmentioning

confidence: 72%

The expression of phospho-AKT1 and phospho-MTOR is associated with a favorable prognosis independent of PTEN expression in intrahepatic cholangiocarcinomas

Lee

Choi

et al. 2012

Modern Pathology

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“…For example, PI3K is positively implicated in apoptosis induction in response to various stimuli, including hypoxia (23), arsenic compounds (24), glucose deprivation (25), and serum withdrawal (26). These findings indicate that PI3K activates two functionally opposite pathways, depending on cell type, nature of stimulus, and activities of other signaling pathways.…”

Section: Introductionmentioning

confidence: 91%

Opposing Roles of c-Jun NH2-Terminal Kinase and p38 Mitogen-Activated Protein Kinase in the Cellular Response to Ionizing Radiation in Human Cervical Cancer Cells

Kim

Choi

Park

et al. 2008

Molecular Cancer Research

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Exposure of cells to ionizing radiation induces activation of multiple signaling pathways that play critical roles in determining cell fate. However, the molecular basis for cell death or survival signaling in response to radiation is unclear at present. Here, we show opposing roles of the c-jun NH 2 -terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) pathways in the mitochondrial cell death in response to ionizing radiation in human cervical cancer cells. Ionizing radiation triggered Bax and Bak activation, Bcl-2 down-regulation, and subsequent mitochondrial cell death. Inhibition of JNK completely suppressed radiation-induced Bax and Bak activation and Bcl-2 down-regulation. Dominant-negative forms of stress-activated protein kinase/extracellular signal-regulated kinase kinase 1 (SEK-1)/mitogen-activated protein kinase kinase-4 (MKK-4) inhibited JNK activation. Radiation also induced phosphoinositide 3-kinase (PI3K) activation. Interestingly, inhibition of PI3K effectively attenuated radiation-induced mitochondrial cell death and increased clonogenic survival. Inhibition of PI3K also suppressed SEK-1/MKK-4 and JNK activation, Bax and Bak activation, and Bcl-2 down-regulation. In contrast, inhibition of p38 MAPK led to enhanced Bax and Bak activation and mitochondrial cell death. RacN17, a dominant-negative form of Rac1, inhibited p38 MAPK activation and increased Bax and Bak activation. Exposure of cells to radiation also induced selective activation of c-Src among Src family kinases. Inhibition of c-Src by pretreatment with Src family kinase inhibitor PP2 or small interfering RNA targeting of c-Src attenuated radiation-induced p38 MAPK and Rac1 activation and enhanced Bax and Bak activation and cell death. Our results support the notion that the PI3K-SEK-1/MKK-4-JNK pathway is required for the mitochondrial cell death in response to radiation, whereas the c-Src-Rac1-p38 MAPK pathway plays a cytoprotective role against mitochondrial cell death.

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“…52 In necrotic cells autophagy is increased. 53 What could trigger autophagy under these conditions?…”

Section: Mtor Energy and Autophagymentioning

confidence: 99%

“…65 Unexpectedly, however, in a rat cardiomyocytederived cell line, the activation of class-I PI3K during glucose deprivation induces the accumulation of autophagic vacuoles and causes cell death. 52 A further degree of complexity is introduced by the observation that in glioma cells containing a Ras mutant (RasG12V) in which several signaling pathways, including the class-I PI3K pathway, were stimulated, autophagic cell death was induced. 71 In contrast, the expression of a Ras mutant (RasG12V, Y40C) that specifically activates class-I PI3K inhibits starvation-induced autophagy in transformed fibroblasts, 72 which fits in with the inhibitory role of class-I PI3K on autophagy in other models (see above).…”

Section: Autophagy and Cell Deathmentioning

confidence: 99%

Autophagy and signaling: their role in cell survival and cell death

2005

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Macroautophagy is a vacuolar, self-digesting mechanism responsible for the removal of long-lived proteins and damaged organelles by the lysosome. The discovery of the ATG genes has provided key information about the formation of the autophagosome, and about the role of macroautophagy in allowing cells to survive during nutrient depletion and/or in the absence of growth factors. Two connected signaling pathways encompassing class-I phosphatidylinositol 3-kinase and (mammalian) target of rapamycin play a central role in controlling macroautophagy in response to starvation. However, a considerable body of literature reports that macroautophagy is also a cell death mechanism that can occur either in the absence of detectable signs of apoptosis (via autophagic cell death) or concomitantly with apoptosis. Macroautophagy is activated by signaling pathways that also control apoptosis. The aim of this review is to discuss the signaling pathways that control macroautophagy during cell survival and cell death.

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Phosphoinositide 3-kinase accelerates autophagic cell death during glucose deprivation in the rat cardiomyocyte-derived cell line H9c2

Cited by 118 publications

References 27 publications

The expression of phospho-AKT1 and phospho-MTOR is associated with a favorable prognosis independent of PTEN expression in intrahepatic cholangiocarcinomas

The expression of phospho-AKT1 and phospho-MTOR is associated with a favorable prognosis independent of PTEN expression in intrahepatic cholangiocarcinomas

Opposing Roles of c-Jun NH2-Terminal Kinase and p38 Mitogen-Activated Protein Kinase in the Cellular Response to Ionizing Radiation in Human Cervical Cancer Cells

Autophagy and signaling: their role in cell survival and cell death

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