Cross-talk between calpain and caspase-3/-7 in cisplatin-induced apoptosis of melanoma cells: a major role of calpain inhibition in cell death protection and p53 status

Although doxorubicin (DOX) is one of the most potent antitumor agents available, its clinical use is limited because of the risk of severe cardiotoxicity often leading to irreversible congestive heart failure. Apoptotic cell death is a key component in DOX-induced cardiotoxicity, but its trigger(s) and mechanisms are poorly understood. Here, we explore the role of peroxynitrite (a reactive oxidant produced from the diffusion-controlled reaction between nitric oxide and superoxide anion) in DOX-induced cell death. Using a well-established in vivo mouse model of DOX-induced acute heart failure, we demonstrate marked increases in myocardial apoptosis (caspase-3 and 9 gene expression, caspase 3 activity, cytochrome-c release, and TUNEL), iNOS but not eNOS and nNOS expression, 3-nitrotyrosine formation and a decrease in myocardial contractility following DOX treatment. Pre-treatment of mice with peroxynitrite scavengers markedly attenuated DOX-induced myocardial cell death and dysfunction without affecting iNOS expression. DOX induced increased superoxide generation and nitrotyrosine formation in the mitochondria, dissipation of mitochondrial membrane potential, apoptosis (cytochrome-C release, annexin V staining, caspase activation, nuclear fragmentation), and disruption of actin cytoskeleton structure in cardiac-derived H9c2 cells. Selective iNOS inhibitors attenuated DOX-induced apoptosis, without affecting increased mitochondrial superoxide generation, whereas NO donors increased DOX-induced cell death in vitro . The peroxynitrite scavengers FeTMPyP and MnTMPyP markedly reduced both DOX- or peroxynitrite-induced nitrotyrosine formation and cell death in vitro , without affecting DOX-induced increased mitochondrial superoxide formation. Thus, peroxynitrite is a major trigger of DOX-induced apoptosis, and its effective neutralization can be of significant therapeutic benefit.

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JNK1 Deficient Insulin-Producing Cells Are Protected against Interleukin-1β-Induced Apoptosis Associated with Abrogated Myc Expression

Journal of Diabetes Research ◽

10.1155/2016/1312705 ◽

2016 ◽

Vol 2016 ◽

pp. 1-15 ◽

Cited By ~ 2

Author(s):

Michala Prause ◽

Christopher Michael Mayer ◽

Caroline Brorsson ◽

Klaus Stensgaard Frederiksen ◽

Nils Billestrup ◽

...

Keyword(s):

Cell Death ◽

Protein Phosphorylation ◽

Cell Apoptosis ◽

Caspase 3 ◽

Protein Family ◽

Interleukin 1Β ◽

Insulin Producing Cells ◽

Induced Apoptosis ◽

Mrna Isoform

The relative contributions of the JNK subtypes in inflammatoryβ-cell failure and apoptosis are unclear. The JNK protein family consists of JNK1, JNK2, and JNK3 subtypes, encompassing many different isoforms. INS-1 cells express JNK1α1, JNK1α2, JNK1β1, JNK1β2, JNK2α1, JNK2α2, JNK3α1, and JNK3α2 mRNA isoform transcripts translating into 46 and 54 kDa isoform JNK proteins. Utilizing Lentiviral mediated expression of shRNAs against JNK1, JNK2, or JNK3 in insulin-producing INS-1 cells, we investigated the role of individual JNK subtypes in IL-1β-inducedβ-cell apoptosis. JNK1 knockdown prevented IL-1β-induced INS-1 cell apoptosis associated with decreased 46 kDa isoform JNK protein phosphorylation and attenuated Myc expression. Transient knockdown of Myc also prevented IL-1β-induced apoptosis as well as caspase 3 cleavage. JNK2 shRNA potentiated IL-1β-induced apoptosis and caspase 3 cleavage, whereas JNK3 shRNA did not affect IL-1β-inducedβ-cell death compared to nonsense shRNA expressing INS-1 cells. In conclusion, JNK1 mediates INS-1 cell death associated with increased Myc expression. These findings underline the importance of differentiated targeting of JNK subtypes in the development of inflammatoryβ-cell failure and destruction.

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Inhibition of Autophagy Enhances the Antitumor Effect of Thioridazine in Acute Lymphoblastic Leukemia Cells

Life ◽

10.3390/life11040365 ◽

2021 ◽

Vol 11 (4) ◽

pp. 365

Author(s):

Carina Colturato-Kido ◽

Rayssa M. Lopes ◽

Hyllana C. D. Medeiros ◽

Claudia A. Costa ◽

Laura F. L. Prado-Souza ◽

...

Keyword(s):

Cell Death ◽

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Clinical Problem ◽

Jurkat Cells ◽

Leukemia Cells ◽

Peripheral Mononuclear Blood ◽

Induced Apoptosis ◽

Cure Rates

Acute lymphoblastic leukemia (ALL) is an aggressive malignant disorder of lymphoid progenitor cells that affects children and adults. Despite the high cure rates, drug resistance still remains a significant clinical problem, which stimulates the development of new therapeutic strategies and drugs to improve the disease outcome. Antipsychotic phenothiazines have emerged as potential candidates to be repositioned as antitumor drugs. It was previously shown that the anti-histaminic phenothiazine derivative promethazine induced autophagy-associated cell death in chronic myeloid leukemia cells, although autophagy can act as a “double-edged sword” contributing to cell survival or cell death. Here we evaluated the role of autophagy in thioridazine (TR)-induced cell death in the human ALL model. TR induced apoptosis in ALL Jurkat cells and it was not cytotoxic to normal peripheral mononuclear blood cells. TR promoted the activation of caspase-8 and -3, which was associated with increased NOXA/MCL-1 ratio and autophagy triggering. AMPK/PI3K/AKT/mTOR and MAPK/ERK pathways are involved in TR-induced cell death. The inhibition of the autophagic process enhanced the cytotoxicity of TR in Jurkat cells, highlighting autophagy as a targetable process for drug development purposes in ALL.

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Reactive oxygen species and caspase activation mediate silica-induced apoptosis in alveolar macrophages

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.2001.280.1.l10 ◽

2001 ◽

Vol 280 (1) ◽

pp. L10-L17 ◽

Cited By ~ 32

Author(s):

Han-Ming Shen ◽

Zhuo Zhang ◽

Qi-Feng Zhang ◽

Choon-Nam Ong

Keyword(s):

Reactive Oxygen Species ◽

Cell Death ◽

Alveolar Macrophages ◽

Caspase 3 ◽

Reactive Oxygen ◽

Parp Cleavage ◽

Oxygen Species ◽

Caspase Activation ◽

Caspase 9 ◽

Induced Apoptosis

Alveolar macrophages (AMs) are the principal target cells of silica and occupy a key position in the pathogenesis of silica-related diseases. Silica has been found to induce apoptosis in AMs, whereas its underlying mechanisms involving the initiation and execution of apoptosis are largely unknown. The main objective of the present study was to examine the form of cell death caused by silica and the mechanisms involved. Silica-induced apoptosis in AMs was evaluated by terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling assay and cell cycle/DNA content analysis. The elevated level of reactive oxygen species (ROS), caspase-9 and caspase-3 activation, and poly(ADP-ribose) polymerase (PARP) cleavage in silica-treated AMs were also determined. The results showed that there was a temporal pattern of apoptotic events in silica-treated AMs, starting with ROS formation and followed by caspase-9 and caspase-3 activation, PARP cleavage, and DNA fragmentation. Silica-induced apoptosis was significantly attenuated by a caspase-3 inhibitor, N-acetyl-Asp-Glu-Val-Asp aldehyde, and ebselen, a potent antioxidant. These findings suggest that apoptosis is an important form of cell death caused by silica exposure in which the elevated ROS level that results from silica exposure may act as an initiator, leading to caspase activation and PARP cleavage to execute the apoptotic process.

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4-Acetyl-12,13-Epoxyl-9-Trichothecene-3,15-Diol from Isaria japonica Mediates Apoptosis of Rat Bladder Carcinoma NBT-II Cells by Decreasing Anti-apoptotic Bcl-2 Expression and Increasing Pro-apoptotic Bax Expression

The American Journal of Chinese Medicine ◽

10.1142/s0192415x0400203x ◽

2004 ◽

Vol 32 (03) ◽

pp. 377-387 ◽

Cited By ~ 2

Author(s):

Hyung-Jin Kim ◽

Seon Il Jang ◽

Young-Jun Kim ◽

Hyun-Ock Pae ◽

Hae-Young Won ◽

...

Keyword(s):

Cell Death ◽

Bladder Carcinoma ◽

Cytotoxic Effect ◽

Caspase 3 ◽

Apoptotic Cell ◽

Morphological Changes ◽

Rat Bladder ◽

Apoptotic Protein ◽

Induction Of Apoptosis ◽

Induced Apoptosis

We studied the effect of 4-acetyl-12,13-epoxyl-9-trichothecene-3,15-diol (AETD) isolated from Isaria japonica, one of the most popular Chinese fungal medicines, on the induction of apoptosis in rat bladder carcinoma NBT-II cells. AETD was cytotoxic to NBT-II cells, and this cytotoxic effect appears to be attributed to its induction of apoptotic cell death, as AETD induced nuclear morphological changes and internucleosomal DNA fragmentation, and increased the proportion of hypodiploid cells and activity of caspase-3. AETD treatment also decreased the expression of the anti-apoptotic protein Bcl-2 and increased the expression of the pro-apoptotic protein Bax. These results provide important information in understanding the mechanism(s) of AETD-induced apoptosis.

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Mechanism of cadmium induced apoptosis in human peripheral blood lymphocytes: The role of p53, Fas and Caspase-3

Environmental Toxicology and Pharmacology ◽

10.1016/j.etap.2013.09.006 ◽

2013 ◽

Vol 36 (3) ◽

pp. 1033-1039 ◽

Cited By ~ 31

Author(s):

Abdullah H. Al-Assaf ◽

Ali M. Alqahtani ◽

Ali A. Alshatwi ◽

Naveed A. Syed ◽

Gowhar Shafi ◽

...

Keyword(s):

Peripheral Blood ◽

Caspase 3 ◽

Human Peripheral Blood ◽

Peripheral Blood Lymphocytes ◽

Blood Lymphocytes ◽

Human Peripheral Blood Lymphocytes ◽

Induced Apoptosis

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Restoration of Defective Cross Talk in ssi2 Mutants: Role of Salicylic Acid, Jasmonic Acid, and Fatty Acids in SSI2-Mediated Signaling

Molecular Plant-Microbe Interactions ◽

10.1094/mpmi.2003.16.11.1022 ◽

2003 ◽

Vol 16 (11) ◽

pp. 1022-1029 ◽

Cited By ~ 42

Author(s):

Pradeep Kachroo ◽

Aardra Kachroo ◽

Ludmila Lapchyk ◽

David Hildebrand ◽

Daniel F. Klessig

Keyword(s):

Cell Death ◽

Salicylic Acid ◽

Jasmonic Acid ◽

Cross Talk ◽

Pr Genes ◽

Exogenous Application ◽

Basal Level Expression ◽

Sa Signaling ◽

Spontaneous Cell Death

The Arabidopsis mutants ssi2 and fab2 are defective in stearoyl ACP desaturase, which causes altered salicylic acid (SA)- and jasmonic acid (JA)-mediated defense signaling. Both ssi2 and fab2 plants show spontaneous cell death, express PR genes constitutively, accumulate high levels of SA, and exhibit enhanced resistance to bacterial and oomycete pathogens. In contrast to constitutive activation of the SA pathway, ssi2 and fab2 plants are repressed in JA-mediated induction of the PDF1.2 gene, which suggests that the SSI2-mediated signaling pathway modulates cross talk between the SA and JA pathways. In this study, we have characterized two recessive nonallelic mutants in the ssi2 background, designated as rdc (restorer of defective cross talk) 2 and rdc8. Both ssi2 rdc mutants are suppressed in constitutive SA signaling, show basal level expression of PR-1 gene, and induce high levels of PDF1.2 in response to exogenous application of JA. Interestingly, while the rdc8 mutation completely abolishes spontaneous cell death in ssi2 rdc8 plants, the ssi2 rdc2 plants continue to show some albeit reduced cell death. Fatty acid (FA) analysis showed a reduction in 16:3 levels in ssi2 rdc8 plants, which suggests that this mutation may limit the flux of FAs into the pro-karyotic pathway of glycerolipid biosynthesis. Both rdc2 and rdc8 continue to accumulate high levels of 18:0, which suggests that 18:0 levels were responsible for neither constitutive SA signaling nor repression of JA-induced expression of the PDF1.2 gene in ssi2 plants. We also analyzed SA and JA responses of the fab2-derived shs1 mutant, which accumulates levels of 18:0 over 50% lower than those in the fab2 plants. Even though fab2 shs1 plants were morphologically bigger than fab2 plants, they expressed PR genes constitutively, showed HR-like cell death, and accumulated elevated levels of SA. However, unlike the ssi2 rdc plants, fab2 shs1 plants were unable to induce high levels of PDF1.2 expression in response to exogenous application of JA. Together, these results show that defective cross talk in ssi2 can be restored by second site mutations and is independent of morphological size of the plants, cell death, and elevated levels of 18:0.

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FKBP51 Affects TNF-Related Apoptosis Inducing Ligand Response in Melanoma

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.718947 ◽

2021 ◽

Vol 9 ◽

Author(s):

Martina Tufano ◽

Elena Cesaro ◽

Rosanna Martinelli ◽

Roberto Pacelli ◽

Simona Romano ◽

...

Keyword(s):

Cell Death ◽

Immune Cells ◽

Histone Deacetylases ◽

Melanoma Cells ◽

Transcriptional Level ◽

Cell Death Pathways ◽

Yin Yang 1 ◽

Immune Precipitation ◽

Induced Apoptosis ◽

Repressor Activity

Melanoma is one of the most immunogenic tumors and has the highest potential to elicit specific adaptive antitumor immune responses. Immune cells induce apoptosis of cancer cells either by soluble factors or by triggering cell-death pathways. Melanoma cells exploit multiple mechanisms to escape immune system tumoricidal control. FKBP51 is a relevant pro-oncogenic factor of melanoma cells supporting NF-κB-mediated resistance and cancer stemness/invasion epigenetic programs. Herein, we show that FKBP51-silencing increases TNF-related apoptosis-inducing ligand (TRAIL)-R2 (DR5) expression and sensitizes melanoma cells to TRAIL-induced apoptosis. Consistent with the general increase in histone deacetylases, as by the proteomic profile, the immune precipitation assay showed decreased acetyl-Yin Yang 1 (YY1) after FKBP51 depletion, suggesting an impaired repressor activity of this transcription factor. ChIP assay supported this hypothesis. Compared with non-silenced cells, a reduced acetyl-YY1 was found on the DR5 promoter, resulting in increased DR5 transcript levels. Using Crispr/Cas9 knockout (KO) melanoma cells, we confirmed the negative regulation of DR5 by FKBP51. We also show that KO cells displayed reduced levels of acetyl-EP300 responsible for YY1 acetylation, along with reduced acetyl-YY1. Reconstituting FKBP51 levels contrasted the effects of KO on DR5, acetyl-YY1, and acetyl-EP300 levels. In conclusion, our finding shows that FKBP51 reduces DR5 expression at the transcriptional level by promoting YY1 repressor activity. Our study supports the conclusion that targeting FKBP51 increases the expression level of DR5 and sensitivity to TRAIL-induced cell death, which can improve the tumoricidal action of immune cells.

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UFL1 Alleviates LPS-Induced Apoptosis by Regulating the NF-κB Signaling Pathway in Bovine Ovarian Granulosa Cells

Biomolecules ◽

10.3390/biom10020260 ◽

2020 ◽

Vol 10 (2) ◽

pp. 260 ◽

Cited By ~ 2

Author(s):

Xinling Wang ◽

Chengmin Li ◽

Yiru Wang ◽

Lian Li ◽

Zhaoyu Han ◽

...

Keyword(s):

Signaling Pathway ◽

Granulosa Cells ◽

Protein Concentration ◽

Caspase 3 ◽

Nuclear Factor Κb ◽

Ovarian Granulosa Cells ◽

Induced Apoptosis ◽

Apoptosis Level ◽

Lps Treatment

Ubiquitin-like modifier 1 ligating enzyme 1 (UFL1) is an E3 ligase of ubiquitin fold modifier 1 (UFM1), which can act together with its target protein to inhibit the apoptosis of cells. Lipopolysaccharides (LPS) can affect the ovarian health of female animals by affecting the apoptosis of ovarian granulosa cells. The physiological function of UFL1 on the apoptosis of bovine (ovarian) granulosa cells (bGCs) remains unclear; therefore, we focused on the modulating effect of UFL1 on the regulation of LPS-induced apoptosis in ovarian granulosa cells. Our study found that UFL1 was expressed in both the nucleus and cytoplasm of bGCs. The results here demonstrated that LPS caused a significant increase in the apoptosis level of bGCs in cows, and also dramatically increased the expression of UFL1. Furthermore, we found that UFL1 depletion caused a significant increase in apoptosis (increased the expression of BAX/BCL-2 and the activity of caspase-3). Conversely, the overexpression of UFL1 relieved the LPS-induced apoptosis. In order to assess whether the inhibition of bGCs apoptosis involved in the nuclear factor-κB (NF-κB) signaling pathway resulted from UFL1, we detected the expression of NF-κB p-p65. LPS treatment resulted in a significant upregulation in the protein concentration of NF-κB p-p65, and knockdown of UFL1 further increased the phosphorylation of NF-κB p65, while UFL1 overexpression significantly inhibited the expression of NF-κB p-p65. Collectively, UFL1 could suppress LPS-induced apoptosis in cow ovarian granulosa cells, likely via the NF-κB pathway. These results identify a novel role of UFL1 in the modulation of bGC apoptosis, which may be a potential signaling target to improve the reproductive health of dairy cows.

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