Necroptosis modulated by autophagy is a predominant form of melanoma cell death induced by sanguilutine

2012 ◽  
Vol 393 (7) ◽  
pp. 647-658 ◽  
Author(s):  
Jindřiška Hammerová ◽  
Stjepan Uldrijan ◽  
Eva Táborská ◽  
Alena Hyršlová Vaculová ◽  
Iva Slaninová
Keyword(s):  
Cell Death ◽  
Therapeutic Potential ◽  
Apoptotic Cell ◽  
Specific Inhibitor ◽  
Melanoma Cells ◽  
Bafilomycin A1 ◽  
Autophagy Induction ◽  
Predominant Type ◽  
Predominant Form ◽  
Lc3 Puncta

Abstract We show that the plant quaternary benzo[c]phenanthridine alkaloid sanguilutine (SL) is a strong inducer of caspase-independent non-apoptotic death in human melanoma cells. Necrostatin-1, a specific inhibitor of necroptosis, completely reversed the cytotoxic effect of SL, suggesting that necroptosis was a predominant type of cell death induced by SL in these cells. In addition, we showed that SL can trigger an autophagic response, as confirmed by GFP-LC3 puncta formation and LC3-II accumulation. Interestingly, we observed a significant decrease in the viability of melanoma cells treated with combination of autophagy inhibitors (3-methyladenine, bafilomycin-A1 and LY294002) and SL. Our results further indicated that autophagy may serve as a pro-survival mechanism, delaying the induction of necroptosis in melanoma cells. The ability of SL to induce caspase-independent non-apoptotic cell death (necroptosis) suggests its possible therapeutic potential in the treatment of apoptosis-resistant melanoma tumours. Furthermore, SL might serve as a useful tool for studying the mechanisms of necroptosis and autophagy induction and the interplay between these two processes.

scholarly journals Mitochondrial targeting of the electrophilic lipid 15-deoxy-Δ12,14prostaglandin J2 increases apoptotic efficacy via redox cell signalling mechanisms

2010 ◽  
Vol 426 (1) ◽  
pp. 31-41 ◽  
Author(s):  
Anne R. Diers ◽  
Ashlee N. Higdon ◽  
Karina C. Ricart ◽  
Michelle S. Johnson ◽  
Anupam Agarwal ◽  
...  
Keyword(s):  
Cell Death ◽  
Therapeutic Potential ◽  
Apoptotic Cell ◽  
Biological Effects ◽  
Cell Signalling ◽  
Mitochondrial Targeting ◽  
Mitochondrial Membrane Depolarization ◽  
Haem Oxygenase ◽  
High Doses ◽  
Fine Tune

Prototypical electrophiles such as the lipid 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) are well recognized for their therapeutic potential. Electrophiles modify signalling proteins in both the cytosol and mitochondrion, which results in diverse cellular responses, including cytoprotective effects and, at high doses, cell death. These findings led us to the hypothesis that targeting electrophiles to specific compartments in the cell could fine-tune their biological effects. To examine this, we synthesized a novel mitochondrially targeted analogue of 15d-PGJ2 (mito-15d-PGJ2) and tested its effects on redox cell signalling. Mito-15d-PGJ2 caused profound defects in mitochondrial bioenergetics and mitochondrial membrane depolarization when compared with 15d-PGJ2. We also found that mito-15d-PGJ2 modified different members of the electrophile-responsive proteome, was more potent at initiating intrinsic apoptotic cell death and was less effective than 15d-PGJ2 at up-regulating the expression of HO-1 (haem oxygenase-1) and glutathione. These results demonstrate the feasibility of modulating the biological effects of electrophiles by targeting the pharmacophore to mitochondria.

scholarly journals Therapeutic Potential of (−)-Agelamide D, a Diterpene Alkaloid from the Marine Sponge Agelas sp., as a Natural Radiosensitizer in Hepatocellular Carcinoma Models

Marine Drugs ◽  
2020 ◽  
Vol 18 (10) ◽  
pp. 500
Author(s):  
Changhoon Choi ◽  
Yeonwoo Cho ◽  
Arang Son ◽  
Sung-Won Shin ◽  
Yeon-Ju Lee ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Death ◽  
Marine Sponge ◽  
Therapeutic Potential ◽  
Apoptotic Cell ◽  
Local Treatment ◽  
Predictive Biomarkers ◽  
Apoptotic Cell Death ◽  
Tumor Growth Inhibition ◽  
Radiation Induced

Radiation therapy (RT) is an effective local treatment for unresectable hepatocellular carcinoma (HCC), but there are currently no predictive biomarkers to guide treatment decision for RT or adjuvant systemic drugs to be combined with RT for HCC patients. Previously, we reported that extracts of the marine sponge Agelas sp. may contain a natural radiosensitizer for HCC treatment. In this study, we isolated (−)-agelamide D from Agelas extract and investigated the mechanism underlying its radiosensitization. (−)-Agelamide D enhanced radiation sensitivity of Hep3B cells with decreased clonogenic survival and increased apoptotic cell death. Furthermore, (−)-agelamide D increased the expression of protein kinase RNA-like endoplasmic reticulum kinase/inositol-requiring enzyme 1α/activating transcription factor 4 (PERK/eIF2α/ATF4), a key pathway of the unfolded protein response (UPR) in multiple HCC cell lines, and augmented radiation-induced UPR signaling. In vivo xenograft experiments confirmed that (−)-agelamide D enhanced tumor growth inhibition by radiation without systemic toxicity. Immunohistochemistry results showed that (−)-agelamide D further increased radiation-induced ATF4 expression and apoptotic cell death, which was consistent with our in vitro finding. Collectively, our results provide preclinical evidence that the use of UPR inducers such as (−)-agelamide D may enhance the efficacy of RT in HCC management.

scholarly journals A Role for H2O2 and TRPM2 in the Induction of Cell Death: Studies in KGN Cells

Antioxidants ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 518 ◽  
Author(s):  
Carsten Theo Hack ◽  
Theresa Buck ◽  
Konstantin Bagnjuk ◽  
Katja Eubler ◽  
Lars Kunz ◽  
...  
Keyword(s):  
Cell Death ◽  
Transient Receptor Potential ◽  
Therapeutic Potential ◽  
Apoptotic Cell ◽  
Receptor Potential ◽  
Granulosa Cell Tumor ◽  
Nadph Oxidase 4 ◽  
Transient Receptor Potential Melastatin ◽  
Trpm2 Channel

Recent studies showed that KGN cells, derived from a human granulosa cell tumor (GCT), express NADPH oxidase 4 (NOX4), an important source of H2O2. Transient receptor potential melastatin 2 (TRPM2) channel is a Ca2+ permeable cation channel that can be activated by H2O2 and plays an important role in cellular functions. It is also able to promote susceptibility to cell death. We studied expression and functionality of TRPM2 in KGN cells and examined GCT tissue microarrays (TMAs) to explore in vivo relevance. We employed live cell, calcium and mitochondrial imaging, viability assays, fluorescence activated cell sorting (FACS) analysis, Western blotting and immunohistochemistry. We confirmed that KGN cells produce H2O2 and found that they express functional TRPM2. H2O2 increased intracellular Ca2+ levels and N-(p-Amylcinnamoyl)anthranilic acid (ACA), a TRPM2 inhibitor, blocked this action. H2O2 caused mitochondrial fragmentation and apoptotic cell death, which could be attenuated by a scavenger (Trolox). Immunohistochemistry showed parallel expression of NOX4 and TRPM2 in all 73 tumor samples examined. The results suggest that GCTs can be endowed with a system that may convey susceptibility to cell death. If so, induction of oxidative stress may be beneficial in GCT therapy. Our results also imply a therapeutic potential for TRPM2 as a drug target in GCTs.

scholarly journals Autophagy Promotes Porcine Parvovirus Replication and Induces Non-Apoptotic Cell Death in Porcine Placental Trophoblasts

Viruses ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 15
Author(s):  
Xiujuan Zhang ◽  
Yingli Xiong ◽  
Jie Zhang ◽  
Ting Shao ◽  
Songbiao Chen ◽  
...  
Keyword(s):  
Cell Death ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Porcine Parvovirus ◽  
Caspase Inhibitor ◽  
Autophagy Flux ◽  
Autophagy Induction ◽  
Cellular Apoptosis ◽  
Infected Cells ◽  
Later Phase

Autophagy plays important roles in the infection and pathogenesis of many viruses, yet the regulatory roles of autophagy in the process of porcine parvovirus (PPV) infection remain unclear. Herein, we show that PPV infection induces autophagy in porcine placental trophoblasts (PTCs). Induction of autophagy by rapamycin (RAPA) inhibited the occurrence of apoptotic cell death, yet promoted viral replication in PPV-infected cells; inhibition of autophagy by 3-MA or ATG5 knockdown increased cellular apoptosis and reduced PPV replication. Interestingly, we found that in the presence of caspase-inhibitor zVAD-fmk, PPV induces non-apoptotic cell death that was characterized by lysosomal damage and associated with autophagy. Induction of complete autophagy flux by RAPA markedly promoted PPV replication compared with incomplete autophagy induced by RAPA plus bafilomycin (RAPA/BAF) in the early phase of PPV infection (24 h.p.i.). Meanwhile, induction of complete autophagy with RAPA increased lysosomal damage and non-apoptotic cell death in the later phase of PPV infection. Therefore, our data suggest that autophagy can enhance PPV replication and promote the occurrence of lysosomal-damage-associated non-apoptotic cell death in PPV-infected porcine placental trophoblasts.

scholarly journals Hypoxia/re-oxygenation-induced, redox-dependent activation of STAT1 (signal transducer and activator of transcription 1) confers resistance to apoptotic cell death via hsp70 induction

2004 ◽  
Vol 380 (1) ◽  
pp. 203-209 ◽  
Author(s):  
Keita TERUI ◽  
Sanae HAGA ◽  
Shin ENOSAWA ◽  
Naomi OHNUMA ◽  
Michitaka OZAKI
Keyword(s):  
Cell Death ◽  
Cell Survival ◽  
Apoptotic Cell ◽  
Specific Inhibitor ◽  
Apoptotic Cell Death ◽  
Janus Kinase ◽  
Serine Phosphorylation ◽  
Dependent Manner ◽  
Signal Transducer ◽  
Hsp70 Induction

STAT1 (signal transducer and activator of transcription 1) is potentially involved in cell survival, as well as cell death, in different types of cells. The present study was designed to examine the effects of STAT1 on hypoxia/re-oxygenation (H/R)-induced cell death and/or survival, and the underlying mechanisms of any such effects. H/R was shown to induce apoptotic cell death of rat hepatocytes. The addition of a STAT1-specific inhibitor, fludarabine, significantly increased the fraction of apoptotic cells after H/R. Following H/R, STAT1 was activated and sequential phosphorylation of Tyr701 and Ser727 was observed, which could be inhibited by the antioxidant N-acetyl-l-cysteine. Tyrosine and serine phosphorylation of STAT1 was mediated by Janus kinase 2 and phosphoinositide 3-kinase/Akt kinase respectively in a redox-dependent manner following H/R. STAT1-induced HSP70 (heat-shock protein 70) expression and the suppression of apoptosis occurred concomitantly. In conclusion, STAT1 activation, in a redox-dependent manner, following H/R may play crucial roles in cell survival, at least partly via HSP70 induction.

scholarly journals Dihydroxyacetone induces G2/M arrest and apoptotic cell death in A375P melanoma cells

2017 ◽  
Vol 33 (3) ◽  
pp. 333-342 ◽  
Author(s):  
Kelly R. Smith ◽  
Molley Granberry ◽  
Marcus C.B. Tan ◽  
Casey L. Daniel ◽  
Natalie R. Gassman
Keyword(s):  
Cell Death ◽  
Apoptotic Cell ◽  
Melanoma Cells ◽  
Apoptotic Cell Death

scholarly journals The lncRNA H19-Derived MicroRNA-675 Promotes Liver Necroptosis by Targeting FADD

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 411
Author(s):  
Rona Harari-Steinfeld ◽  
Maytal Gefen ◽  
Alina Simerzin ◽  
Elina Zorde-Khvalevsky ◽  
Mila Rivkin ◽  
...  
Keyword(s):  
Cell Death ◽  
Apoptotic Cell ◽  
Specific Inhibitor ◽  
Kinase Domain ◽  
Tumor Promoter ◽  
Death Domain ◽  
Liver Inflammation ◽  
Interacting Protein ◽  
Important Regulator ◽  
Cell Death Signaling

The H19-derived microRNA-675 (miR-675) has been implicated as both tumor promoter and tumor suppressor and also plays a role in liver inflammation. We found that miR-675 promotes cell death in human hepatocellular carcinoma (HCC) cell lines. We show that Fas-associated protein with death domain (FADD), a mediator of apoptotic cell death signaling, is downregulated by miR-675 and a negative correlation exists between miR-675 and FADD expression in mouse models of HCC (p = 0.014) as well as in human samples (p = 0.017). We demonstrate in a mouse model of liver inflammation that overexpression of miR-675 promotes necroptosis, which can be inhibited by the necroptosis-specific inhibitor Nec-1/Nec-1s. miR-675 induces the level of both p-MLKL (Mixed Lineage Kinase Domain-Like Pseudokinase) and RIP3 (receptor-interacting protein 3), which are key signaling molecules in necroptosis, and enhances MLKL binding to RIP3. miR-675 also inhibits the levels of cleaved caspases 8 and 3, suggesting that miR-675 induces a shift from apoptosis to a necroptotic cellular pathway. In conclusion, downregulation of FADD by miR-675 promotes liver necroptosis in response to inflammatory signals. We propose that this regulation cascade can stimulate and enhance the inflammatory response in the liver, making miR-675 an important regulator in liver inflammation and potentially also in HCC.

scholarly journals Inhibition of Drp1 Sensitizes Cancer Cells to Cisplatin-Induced Apoptosis through Transcriptional Inhibition of c-FLIP Expression

Molecules ◽  
2020 ◽  
Vol 25 (24) ◽  
pp. 5793
Author(s):  
Seon Min Woo ◽  
Kyoung-jin Min ◽  
Taeg Kyu Kwon
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Apoptotic Cell ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Combined Treatment ◽  
Ectopic Expression ◽  
Specific Inhibitor ◽  
Apoptotic Cell Death ◽  
Induced Apoptosis

Mitochondrial fragmentation occurs during the apoptosis. Dynamin-related protein 1 (Drp1) acts as an important component in mitochondrial fission machinery and can regulate various biological processes including apoptosis, cell cycle, and proliferation. The present study demonstrates that dysfunction of mitochondrial dynamics plays a pivotal role in cisplatin-induced apoptosis. Inhibiting the mitochondrial fission with the specific inhibitor (Mdivi-1) did not affect apoptotic cell death in low concentrations (<10 μM). Interestingly, mdivi-1 enhanced cisplatin-induced apoptosis in cancer cells, but not in normal cells. Particularly in the presence of mdivi-1, several human cancer cell lines, including renal carcinoma cell line Caki-1, became vulnerable to cisplatin by demonstrating the traits of caspase 3-dependent apoptosis. Combined treatment induced downregulation of c-FLIP expression transcriptionally, and ectopic expression of c-FLIP attenuated combined treatment-induced apoptotic cell death with mdivi-1 plus cisplatin. Collectively, our data provide evidence that mdivi-1 might be a cisplatin sensitizer.

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