Phospholipidosis and down-regulation of the PI3-K/PDK-1/Akt signalling pathway are vitamin E inhibitable events associated with 7-ketocholesterol-induced apoptosis

Véjux, Anne; Guyot, Stéphane; Montange, Thomas; Riedinger, Jean-Marc; Kahn, Edmond; Lizard, Gérard

doi:10.1016/j.jnutbio.2007.12.001

Cited by 87 publications

(60 citation statements)

References 74 publications

(112 reference statements)

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“…To further determine the role of PI3K/ Akt/mTOR signaling in B10-triggered autophagy, we used a-tocopherol to prevent the B10-mediated inhibition of the PI3K/Akt/mTOR pathway, as a-tocopherol has previously been reported to stabilize lipid rafts, thereby stimulating PI3K activity and thus PI3K/Akt/mTOR signaling. 15 Addition of a-tocopherol partly preserved phosphorylation of Akt and S6, reduced LC3 lipidation upon B10 treatment and significantly reduced B10-induced lysosomal permeabilization and cell death (Supplementary Figure S3). Because a-tocopherol indirectly stimulates PI3K signaling and can exert additional functions, for example, antioxidant functions, 16 we also knocked down TSC2 to activate mTOR.…”

Section: Resultsmentioning

confidence: 95%

Impairment of lysosomal integrity by B10, a glycosylated derivative of betulinic acid, leads to lysosomal cell death and converts autophagy into a detrimental process

et al. 2012

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In this study, we report a novel mechanism of action for a cytotoxic derivative of betulinic acid (BA). B10 is a semi-synthetic glycosylated derivative of BA selected for its enhanced cytotoxic activity. Interestingly, although B10 induces apoptosis, caspase-3 downregulation incompletely prevents B10-induced cell death, Bcl-2 overexpression fails to protect cells and DNA fragmentation rates do not reflect cell death rates in contrast to cytoplasmic membrane permeabilization. These results implicate that apoptotic and non-apoptotic cell death coexist upon B10 treatment. Unexpectedly, we found that B10 induces autophagy and also abrogates the autophagic flux. B10 destabilizes lysosomes as shown by Lysotracker Red staining and by cathepsin Z and B release from lysosomes into the cytoplasm. Consistently, the cathepsin inhibitor Ca074Me significantly decreases B10-induced cell death, further supporting the fact that the release of lysosomal enzymes contributes to B10-triggered cell death. Downregulation of ATG7, ATG5 or BECN1 by RNAi significantly decreases caspase-3 activation, lysosomal permeabilization and cell death. Thus, by concomitant induction of autophagy and inhibition of the autophagic flux, B10 turns autophagy into a cell death mechanism. These findings have important implications for the therapeutic exploitation of BA derivatives, particularly in apoptosis-resistant cancers. Bioactive natural compounds or their semi-synthetic derivatives offer a considerable therapeutic potential against cancer.1 Among these, betulinic acid (BA), a triterpenoid initially derived from white birch tree, has received attention because of its multiple biological activities in mammalian cells. The pluripotency of BA is of great interest, as this compound is active against HIV, parasitic diseases and cancer.2-5 Nevertheless, the therapeutic application of this drug is currently limited because of its poor solubility in aqueous solvents and an ill-defined mode of action. To overcome these limitations, a wide variety of semi-synthetic derivatives of BA has been generated to improve its pharmacological properties for in vivo studies. In addition, detailed studies are being performed to elucidate the mechanisms of action underlying their cytotoxic activity. To date, BA and its derivatives have been reported to induce cell death in cancer cells via the activation of the intrinsic pathway of apoptosis.6 Accordingly, BA triggers the release of pro-apoptotic factors, such as cytochrome-c, from the mitochondria supposedly by interacting with the permeability pore transition complex and by modifying the balance of pro-and anti-apoptotic proteins of the Bcl-2 protein family. 6 In addition, BA and its derivatives appear to interfere with multiple signaling pathways involved in survival. PI3K, NF-kB and lipid metabolism are modulated by BA-related compounds, but whether and how these effects contribute to cell death is unknown.7-10 A better understanding of the mechanism of action of these compounds is critical to promote their therapeutic...

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Section: Resultsmentioning

confidence: 95%

Impairment of lysosomal integrity by B10, a glycosylated derivative of betulinic acid, leads to lysosomal cell death and converts autophagy into a detrimental process

et al. 2012

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“…It has also been shown that 24S-OHC acts as a ligand of the nuclear receptor liver X receptor, which regulates the gene expression of proteins involved in cholesterol transport in cell membrane (13). 7-Ketocholesterol, nonenzymatic oxidation product of cholesterol, has been shown to induce cell death through inactivation of the phosphatidylinositol 3-kinase/Akt signaling pathway (14), which is considered to be highly specific to lipid raft domains (15). 24S-OHC has been shown to possess potent neurotoxicity (16); however, the molecular mechanisms of the induction of neurotoxicity, particularly in the form of cell death, are less clearly defined.…”

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confidence: 99%

24(S)-Hydroxycholesterol Induces Neuronal Cell Death through Necroptosis, a Form of Programmed Necrosis

Yamanaka

Saito

Yamamori

et al. 2011

Journal of Biological Chemistry

102

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“…These structures are thought to be involved in cellular signaling mechanisms (8,9). It is worthy of note that 7-ketocholesterol has been shown to induce cell death through inactivation of the phosphatidylinositol 3-kinase/Akt signaling pathway (10), which is known to be highly specific to lipid raft domains (9).…”

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confidence: 99%

“…Although several studies have shown that vitamin E has the ability to counteract the pro-apoptotic effect of 7-ketocholesterol in cultured cells (10,13), the underlying molecular mechanism is unclear.…”

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confidence: 99%

7-Ketocholesterol Incorporation into Sphingolipid/Cholesterol-enriched (Lipid Raft) Domains Is Impaired by Vitamin E

Royer

Lemaire-Ewing

Desrumaux

et al. 2009

Journal of Biological Chemistry

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Cholesterol oxides, in particular 7-ketocholesterol, are proatherogenic compounds that induce cell death in the vascular wall when localized in lipid raft domains of the cell membrane. Deleterious effects of 7-ketocholesterol can be prevented by vitamin E, but the molecular mechanism involved is unclear. In this study, unlike ␥-tocopherol, the ␣-tocopherol vitamin E form was found to prevent 7-ketocholesterol-mediated apoptosis of A7R5 smooth muscle cells. To be operative, ␣-tocopherol needed to be added to the cells before 7-ketocholesterol, and its anti-apoptotic effect was reduced and even suppressed when added together or after 7-ketocholesterol, respectively. Both pre-and co-treatment of the cells with ␣-tocopherol resulted in the redistribution of 7-ketocholesterol out of the sphingolipid/cholesterol-enriched (lipid raft) domains. In turn, fewer amounts of ␣-tocopherol associated with lipid rafts on 7-ketocholesterol-pretreated cells compared with untreated cells, with no prevention of cell death in this case. In further support of the implication of lipid raft domains, the dephosphorylation/inactivation of Akt-PKB was involved in the 7-ketocholesterol-induced apoptosis. Akt-PKB dephosphorylation was prevented by ␣-tocopherol, but not ␥-tocopherol pretreatment.

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Phospholipidosis and down-regulation of the PI3-K/PDK-1/Akt signalling pathway are vitamin E inhibitable events associated with 7-ketocholesterol-induced apoptosis

Cited by 87 publications

References 74 publications

Impairment of lysosomal integrity by B10, a glycosylated derivative of betulinic acid, leads to lysosomal cell death and converts autophagy into a detrimental process

Impairment of lysosomal integrity by B10, a glycosylated derivative of betulinic acid, leads to lysosomal cell death and converts autophagy into a detrimental process

24(S)-Hydroxycholesterol Induces Neuronal Cell Death through Necroptosis, a Form of Programmed Necrosis

7-Ketocholesterol Incorporation into Sphingolipid/Cholesterol-enriched (Lipid Raft) Domains Is Impaired by Vitamin E

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