Intracellular acidification by inhibition of the Na+/H+-exchanger leads to caspase-independent death of cerebellar granule neurons resembling paraptosis

Schneider, Dagmar; Gerhardt, Ellen; Bock, Jörg; Müller, Michael G.; Wolburg, Hartwig; Läng, Florian; Schulz, Jörg B.

doi:10.1038/sj.cdd.4401377

Cited by 55 publications

(45 citation statements)

References 35 publications

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“…Seven clusters showed responses with opposite signs (Fig. 2a, clusters 1,6,7,11,14,15,17), whereas only clusters 10 and 13 displayed genes exhibiting similar responses to A0 and cisplatin. The statistical search for genes with a differential response to A0 and cisplatin yielded 386 transcripts, corresponding to 359 genes, grouped by FLAME in 5 clusters (Fig.…”

Section: Differential Sensitivities Of Human Cancer Cells To A0 Andmentioning

confidence: 99%

The Thioxotriazole Copper(II) Complex A0 Induces Endoplasmic Reticulum Stress and Paraptotic Death in Human Cancer Cells

Tardito

Isella

Medico

et al. 2009

Journal of Biological Chemistry

120

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The copper(II) complex A0 induces a type of non-apoptotic cell death also known as paraptosis. Paraptosis involves extensive endoplasmic reticulum vacuolization in the absence of caspase activation. A wide panel of human cancer cell lines was used to demonstrate differences in cytotoxicity by the paraptosis-inducing drug A0 and the metal-based pro-apoptotic drug cisplatin. Gene expression profiling of the human fibrosarcoma HT1080 cells showed that, while cisplatin induced p53 targets, A0 up-regulated genes involved in the unfolded protein response (UPR) and response to heavy metals. The cytotoxic effects of A0 were associated with inhibition of the ubiquitinproteasome system and accumulation of ubiquitinylated proteins, in a manner dependent on protein synthesis. Cycloheximide inhibited the accumulation of ubiquitinylated proteins and hampered A0-induced cell death process. The occurrence of the UPR during A0-induced death process was shown by the increased abundance of spliced XBP1 mRNA, transient eIF2␣ phosphorylation, and a series of downstream events, including attenuation of global protein synthesis and increased expression of ATF4, CHOP, BIP, and GADD34. Mouse embryonic fibroblasts expressing a mutant eIF2␣, which could not be phosphorylated, were more resistant to A0 than wild type cells, pointing to a pro-death role of eIF2␣ phosphorylation. A0 may thus represent the prototypical member of a new class of compounds that cause paraptotic cell death via mechanisms involving eIF2␣ phosphorylation and the UPR.

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Section: Differential Sensitivities Of Human Cancer Cells To A0 Andmentioning

confidence: 99%

The Thioxotriazole Copper(II) Complex A0 Induces Endoplasmic Reticulum Stress and Paraptotic Death in Human Cancer Cells

Tardito

Isella

Medico

et al. 2009

Journal of Biological Chemistry

120

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“…47 Inhibition of the Na þ /H þ antiporter has been noted to induce paraptosis in cerebellar neurons. 48 When BK channels are fully engaged in response to the monocyte mediators, the cell remains swollen. The cell expends more ATP to expel the unwanted Na þ ions.…”

Section: Cell Cytotoxicity Occurred After 8-12 H Of Continuous Bk Chamentioning

confidence: 99%

Human monocytes kill M-CSF-expressing glioma cells by BK channel activation

Hoa

Zhang

Delgado

et al. 2007

Laboratory Investigation

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In this study, human monocytes/macrophages were observed to kill human U251 glioma cells expressing membrane macrophage colony-stimulating factor (mM-CSF) via a swelling and vacuolization process called paraptosis. Human monocytes responded to the mM-CSF-transduced U251 glioma cells, but not to viral vector control U251 glioma cells (U251-VV), by producing a respiratory burst within 20 min. Using patch clamp techniques, functional big potassium (BK) channels were observed on the membrane of the U251 glioma cell. It has been previously reported that oxygen indirectly regulates BK channel function. In this study, it was demonstrated that prolonged BK channel activation in response to the respiratory burst induced by monocytes initiates paraptosis in selected glioma cells. Forced BK channel opening within the glioma cells by BK channel activators (phloretin or pimaric acid) induced U251 glioma cell swelling and vacuolization occurred within 30 min. U251 glioma cell cytotoxicity, induced by using BK channel activators, required between 8 and 12 h. Swelling and vacuolization induced by phloretin and pimaric acid was prevented by iberiotoxin, a specific BK channel inhibitor. Confocal fluorescence microscopy demonstrated BK channels co-localized with the endoplasmic reticulum and mitochondria, the two targeted organelles affected in paraptosis. Iberiotoxin prevented monocytes from producing death in mM-CSF-expressing U251glioma cells in a 24 h assay. This study demonstrates a novel mechanism whereby monocytes can induce paraptosis via the disruption of internal potassium ion homeostasis.

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“…Because nowadays, cell death is no longer defined by morphologic features but by signaling pathways, the precise way of podocyte podoptosis other than apoptosis remains unknown. 27 On the basis of the morphologic signature of MDM2-deficient podocytes (massive cytoplasmic vacuolization and signs of ER stress), it may be currently classified as what has been called paraptosis-like, 28,29 but the associated signaling events remain to be identified. We conclude that podocytes need MDM2 to maintain homeostasis and long-term survival.…”

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confidence: 99%

Murine Double Minute-2 Prevents p53-Overactivation-Related Cell Death (Podoptosis) of Podocytes

Thomasová

Bruns

Kretschmer

et al. 2015

Journal of the American Society of Nephrology

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Murine double minute-2 (MDM2), an E3 ligase that regulates the cell cycle and inflammation, is highly expressed in podocytes. In podocyte injury, MDM2 drives podocyte loss by mitotic catastrophe, but the function of MDM2 in resting podocytes has not been explored. Here, we investigated the effects of podocyte MDM2 deletion in vitro and in vivo. In vitro, MDM2 knockdown by siRNA caused increased expression of p53 and podocyte death, which was completely rescued by coknockdown of p53. Apoptosis, pyroptosis, pyronecrosis, necroptosis, ferroptosis, and parthanatos were excluded as modes of occurrence for this p53-overactivationrelated cell death (here referred to as podoptosis). Podoptosis was associated with cytoplasmic vacuolization, endoplasmic reticulum stress, and dysregulated autophagy (previously described as paraptosis). MDM2 knockdown caused podocyte loss and proteinuria in a zebrafish model, which was consistent with the phenotype of podocyte-specific MDM2-knockout mice that also showed the aforementioned ultrastructual podocyte abnormalities before and during progressive glomerulosclerosis. The phenotype of both animal models was entirely rescued by codeletion of p53. We conclude that MDM2 maintains homeostasis and long-term survival in podocytes by preventing podoptosis, a p53-regulated form of cell death with unspecific features previously classified as paraptosis.

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Intracellular acidification by inhibition of the Na+/H+-exchanger leads to caspase-independent death of cerebellar granule neurons resembling paraptosis

Cited by 55 publications

References 35 publications

The Thioxotriazole Copper(II) Complex A0 Induces Endoplasmic Reticulum Stress and Paraptotic Death in Human Cancer Cells

The Thioxotriazole Copper(II) Complex A0 Induces Endoplasmic Reticulum Stress and Paraptotic Death in Human Cancer Cells

Human monocytes kill M-CSF-expressing glioma cells by BK channel activation

Murine Double Minute-2 Prevents p53-Overactivation-Related Cell Death (Podoptosis) of Podocytes

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