Apoptosis induced by NAD depletion is inhibited by KN-93 in a CaMKII-independent manner

Takeuchi, Mikio; Yamamoto, Tomoko

doi:10.1016/j.yexcr.2015.05.019

Cited by 17 publications

(12 citation statements)

References 24 publications

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“…Many pro-apoptotic proteins were found activated when NAMPT is inhibited in leukemias, multiple myeloma, breast cancer, and lymphoma cells (57–64). It has been found that NAMPT inhibition-mediated apoptosis requires functional apoptotic machinery because blocking apoptosis with several factors such as: L-type calcium channels with verapamil or nimodipine, capase 3 with Z-Asp-Glu Val-Asp-fluoromethylketone, capase 9 with Z-Leu-Glu-His-Asp-fluoromethylketone, or the mitochondrial permeability transition with bongkrekic acid blocks the effect of NAMPT inhibition-mediated apoptosis (62, 64).…”

Section: Nampt In Cancermentioning

confidence: 99%

NAMPT as a Dedifferentiation-Inducer Gene: NAD+ as Core Axis for Glioma Cancer Stem-Like Cells Maintenance

et al. 2019

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Glioma Cancer Stem-Like Cells (GSCs) are a small subset of CD133 + cells with self-renewal properties and capable of initiating new tumors contributing to Glioma progression, maintenance, hierarchy, and complexity. GSCs are highly resistant to chemo and radiotherapy. These cells are believed to be responsible for tumor relapses and patients' fatal outcome after developing a recurrent Glioblastoma (GBM) or High Grade Glioma (HGG). GSCs are cells under replicative stress with high demands on NAD + supply to repair DNA, maintain self-renewal capacity and to induce tumor plasticity. NAD + feeds Poly-ADP polymerases (PARP) and NAD + -dependent deacetylases (SIRTUINS) contributing to GSC phenotype. This energetic core axis is mainly controlled by the rate-limiting enzyme nicotinamide phosphoribosyltransferase (NAMPT), an important oncogene contributing to tumor dedifferentiation. Targeting GSCs depicts a new frontier in Glioma therapy; hence NAMPT could represent a key regulator for GSCs maintenance. Its inhibition may attenuate GSCs properties by decreasing NAD + supply, consequently contributing to a better outcome together with current therapies for Glioma control.

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Section: Nampt In Cancermentioning

confidence: 99%

NAMPT as a Dedifferentiation-Inducer Gene: NAD+ as Core Axis for Glioma Cancer Stem-Like Cells Maintenance

et al. 2019

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“…NAMPT inhibition-induced NAD depletion results in broad metabolic defects and has been shown to reduce mitochondrial membrane potential which can subsequently lead to cell death [25, 28, 31, 40]. We demonstrate that also in EwS cells, FK866 treatment leads to mitochondrial dysfunction (Figure 3), DNA synthesis blockade (Supplementary Figure 2A), and cell death (Figure 4A and Supplementary Figure 2B).…”

Section: Resultsmentioning

confidence: 64%

“…Several different cell type specific mechanisms have previously been reported, including autophagy, oncosis, necrosis and apoptosis [25, 28, 31, 40]. Absence of PARP1 cleavage excludes classical apoptosis for FK866 induced loss of EwS viability.…”

Section: Discussionmentioning

confidence: 99%

EWS-FLI1 confers exquisite sensitivity to NAMPT inhibition in Ewing sarcoma cells

et al. 2017

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Ewing sarcoma (EwS) is the second most common bone cancer in children and adolescents with a high metastatic potential. EwS development is driven by a specific chromosomal translocation resulting in the generation of a chimeric EWS-ETS transcription factor, most frequently EWS-FLI1.Nicotinamide adenine dinucleotide (NAD) is a key metabolite of energy metabolism involved in cellular redox reactions, DNA repair, and in the maintenance of genomic stability. This study describes targeting nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of NAD synthesis, by FK866 in EwS cells. Here we report that blocking NAMPT leads to exhaustive NAD depletion in EwS cells, followed by a metabolic collapse and cell death. Using conditional EWS-FLI1 knockdown by doxycycline-inducible shRNA revealed that EWS-FLI1 depletion significantly reduces the sensitivity of EwS cells to NAMPT inhibition. Consistent with this finding, a comparison of 7 EwS cell lines of different genotypes with 5 Non-EwS cell lines and mesenchymal stem cells revealed significantly higher FK866 sensitivity of EWS-ETS positive EwS cells, with IC50 values mostly below 1nM.Taken together, our data reveal evidence of an important role of the NAMPT-mediated NAD salvage pathway in the energy homeostasis of EwS cells and suggest NAMPT inhibition as a potential new treatment approach for Ewing sarcoma.

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“…It has been reported that KN-93 could prevent the activation of CaMKII (Takeuchi and Yamamoto, 2015; Li J. et al, 2016). In our next study, we found that inhibition of CaMKII by KN-93 could reduce the activity of Pin1 and retinal neuronal RN.…”

Section: Discussionmentioning

confidence: 99%

Pin1 Is Regulated by CaMKII Activation in Glutamate-Induced Retinal Neuronal Regulated Necrosis

Wang

Liao

Huang

et al. 2019

Front. Cell. Neurosci.

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In our previous study, we reported that peptidyl-prolyl isomerase 1 (Pin1)-modulated regulated necrosis (RN) occurred in cultured retinal neurons after glutamate injury. In the current study, we investigated the role of calcium/calmodulin-dependent protein kinase II (CaMKII) in Pin1-modulated RN in cultured rat retinal neurons, and in an animal in vivo model. We first demonstrated that glutamate might lead to calcium overloading mainly through ionotropic glutamate receptors activation. Furthermore, CaMKII activation induced by overloaded calcium leads to Pin1 activation and subsequent RN. Inactivation of CaMKII by KN-93 (KN, i.e., a specific CaMKII inhibitor) application can decrease the glutamate-induced retinal neuronal RN. Finally, by using an animal in vivo model, we also demonstrated the important role of CaMKII in glutamate-induced RN in rat retina. In addition, flash electroretinogram results provided evidence that the impaired visual function induced by glutamate can recover after CaMKII inhibition. In conclusion, CaMKII is an up-regulator of Pin1 and responsible for the RN induced by glutamate. This study provides further understanding of the regulatory pathway of RN and is a complementary mechanism for Pin1 activation mediated necrosis. This finding will provide a potential target to protect neurons from necrosis in neurodegenerative diseases, such as glaucoma, diabetic retinopathy, and even central nervous system diseases.

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Apoptosis induced by NAD depletion is inhibited by KN-93 in a CaMKII-independent manner

Cited by 17 publications

References 24 publications

NAMPT as a Dedifferentiation-Inducer Gene: NAD+ as Core Axis for Glioma Cancer Stem-Like Cells Maintenance

NAMPT as a Dedifferentiation-Inducer Gene: NAD+ as Core Axis for Glioma Cancer Stem-Like Cells Maintenance

EWS-FLI1 confers exquisite sensitivity to NAMPT inhibition in Ewing sarcoma cells

Pin1 Is Regulated by CaMKII Activation in Glutamate-Induced Retinal Neuronal Regulated Necrosis

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