Mechanisms Regulating Cell Death Research Articles

Radiotherapy-induced ferroptosis for cancer treatment.

Ferroptosis is a regulated cell death mechanism controlled by iron, amino acid and reactive oxygen species metabolisms, which is very relevant for cancer therapy. Radiotherapy-induced ferroptosis is critical for tumor suppression and several preclinical studies have demonstrated that the combination of ionizing radiation with small molecules or nano-systems is effective in combating cancer growth and overcoming drug or ionizing radiation resistance. Here, we briefly overview the mechanisms of ferroptosis and the cross-talk existing between the cellular pathways activated by ferroptosis and those induced by radiotherapy. Lastly, we discuss the recently reported combinational studies involving radiotherapy, small molecules as well as nano-systems and report the recent findings achieved in this field for the treatment of tumors.

Identification of immunogenic cell death-associated subtypes and characterization of the tumor microenvironment in endometrial cancer.

Immunogenic cell death (ICD) is one of the mechanisms regulating cell death, which activates adaptive immunity in immunocompetent hosts and is associated with tumor progression, prognosis and therapeutic response. Endometrial cancer (EC) is one of the most common malignancies of the female genital tract, and the potential role of immunogenic cell death-related genes (IRGs) in the tumor microenvironment (TME) remains unclear. We describe the variation of IRGs and assess the expression patterns in EC samples from The Cancer Genome Atlas and Gene Expression Omnibus cohorts. Based on the expression of 34 IRGs, we identified two different ICD-related clusters and subsequently differentially expressed genes between the two ICD-related clusters were used for the identification of two ICD gene clusters. We identified the clusters and found that alterations in the multilayer IRG were associated with patient prognosis and TME cell infiltration characteristics. On this basis, ICD score risk scores were calculated, and ICD signatures were constructed and validated for their predictive power in EC patients. To help clinicians better apply the ICD signature, an accurate nomogram was constructed. The low ICD risk group was characterized by high microsatellite instability, high tumor mutational load, high IPS score and stronger immune activation. Our comprehensive analysis of IRGs in EC patients suggested a potential role in the tumor immune interstitial microenvironment, clinicopathological features and prognosis. These findings may improve our understanding of the role of ICDs, and provide a new basis for assessing prognosis and developing more effective immunotherapeutic strategies in EC.

Kinases control of regulated cell death revealing druggable targets for Parkinson's disease.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder in the world. Motor impairment seen in PD is associated with dopaminergic neurotoxicity in the striatum, and dopaminergic neuronal death in the substantia nigra pars compacta. Cell death has a significant effect on the development and progression of PD. Extensive research over the last few decades has unveiled new regulated cell death (RCD) mechanisms that are not dependent on apoptosis such as necroptosis, ferroptosis, and others. In this review, we will overview the mechanistic pathways of different types of RCD. Unlike accidental cell death, RCD subroutines can be regulated and the RCD-associated kinases are potential druggable targets. Hence, we will address an overview and analysis of different kinases regulating apoptosis such as receptor-interacting protein kinase 1 (RIPK-1), RIPK3, mixed lineage kinase (MLK), Ataxia telangiectasia muted (ATM), cyclin-dependent kinase (CDK), death-associated protein kinase 1 (DAPK1), Apoptosis-signaling kinase-1 (ASK-1), and Leucine-rich repeat kinase-2 (LRRK2). In addition to the role of RIPK1, RIPK3, and Mixed Lineage Kinase Domain like Pseudokinase (MLKL) in necroptosis. We also overview functions of AMP-kinase (AMPK), protein kinase C (PKC), RIPK3, and ATM in ferroptosis. We will recap the anti-apoptotic, anti-necroptotic, and anti-ferroptotic effects of different kinase inhibitors in different models of PD. Finally, we will discuss future challenges in the repositioning of kinase inhibitors in PD. In conclusion, this review kicks-start targeting RCD from a kinases perspective, opening novel therapeutic disease-modifying therapeutic avenues for PD.

A Cuproptosis-Related lncRNAs Signature Could Accurately Predict Prognosis in Patients with Clear Cell Renal Cell Carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancers. As cuproptosis, a new cell death mechanism proposed recently, differs from all other known mechanisms regulating cell death, we aimed to create prognostic markers using cuproptosis-related long non-coding ribonucleic acids (RNAs; lncRNAs) and elucidate the molecular mechanism. Data from transcriptome RNA sequencing of ccRCC samples and the relevant clinical data were downloaded from The Cancer Genome Atlas, and Pearson's correlation analysis was implemented to obtain the cuproptosis-related lncRNAs. Then, univariate Cox, multivariate Cox, and Least Absolute Shrinkage and Selection Operator Cox analyses were performed to construct the risk signatures. The cuproptosis-related lncRNAs predictive signature was evaluated with receiver operating characteristic curves and subgroup analysis. Finally, Gene Set Enrichment Analysis (GSEA), single-sample GSEA (ssGSEA), tumor immune microenvironment (TIME), and immune checkpoints were performed to explore the relationship between immunity and patient prognosis. Five cuproptosis-related lncRNAs, including FOXD2-AS1, LINC00460, AC091212.1, AC007365.1, and AC026401.3, were used to construct the signature. In the training and test sets, low-risk groups (as identified by a risk score lower than the median) demonstrated a better prognosis with an area under the curve for 1-, 3-, and 5-year survival being 0.793, 0.716, and 0.719, respectively. GSEA analysis suggested significant enrichment of the tricarboxylic acid cycle and metabolism-related pathways in the low-risk group. Besides, both ssGSEA and TIME suggested that the high-risk group exhibited more active immune infiltration. We proposed a cuproptosis-related lncRNAs signature, which had the potential for prognoses and prediction. Our findings might contribute to elucidating potential genomic biomarkers and targets for future therapies in the cuproptosis-related signaling pathways.

An Ascovirus Utilizes Different Types of Host Larval Regulated Cell Death Mechanisms To Produce and Release Vesicles.

Ascoviruses are insect-specific viruses that are thought to utilize the cellular apoptotic processes of host larvae to produce numerous virion-containing vesicles. In this study, we monitored the in vivo infection processes of Heliothis virescens ascovirus 3h (HvAV-3h) to illustrate the regulated cell death (RCD) of host cells. Transmission electron microscopic observations did not reveal any morphological markers of apoptosis in the fat bodies or hemocytes of HvAV-3h-infected Helicoverpa armigera or Spodoptera exigua larvae. However, several hemocytes showed the morphological criteria for necrosis and/or pyroptosis. Further in vitro biochemical tests were performed to confirm the RCD type of host cells after infection with HvAV-3h. Different morphological characteristics were found between the early (prior to 24 hours post-infection, [hpi]) and later (48 to 120 hpi) stages in both HvAV-3h infected larval fat bodies and hemocytes. In the early stages, the virions could only be found in several adipohemocytes, and the fat bodies were cleaving their contained lipid inclusions into small lipid dots. In the later stage, both fat bodies and hemocytes were filled with numerous virions. According to the morphological characteristics of HvAV-3h infected larval fat bodies or hemocytes, the pathogenic characteristics and infection patterns of HvAV-3h in the host larvae were described, and the systematic pathogenic mode of ascovirus infection was refined in this study. This study details the complete infection process of ascoviruses, which provides insights into the relationship between a pathogenesis of an insect virus and the RCD of different host tissues at different stages of infection. IMPORTANCE Viruses and other pathogens can interrupt host cellular apoptosis to gain benefits, such as sufficient resources and a stable environment that enables them to complete their replication and assembly. It is unusual for viruses to code proteins with homology to caspases, which are commonly recognized as apoptosis regulators. Ascoviruses are insect viruses with special cytopathology, and they have been hypothesized to induce apoptosis in their host larvae via coding a caspase-like protein. This enables them to utilize the process of cellular apoptosis to facilitate vesicle formation and replication. However, our previous studies revealed different trends. The fat bodies and hemocytes of Heliothis virescens ascovirus 3h (HvAV-3h)-infected larvae did not show any morphological markers of apoptosis but did display necrosis and/or pyroptosis morphological characteristics. The pathogenic characteristics and infection patterns of HvAV-3h in the host larvae were described, which can help us understand the relationship between the pathogenesis of an insect virus and host RCD.

High expression of cuproptosis-related gene FDX1 in relation to good prognosis and immune cells infiltration in colon adenocarcinoma (COAD)

BackgroundCuproptosis induced by FDX1 is a newly discovered mechanism regulating cell death. However, the role of FDX1 in the pathogenesis of colon adenocarcinoma (COAD) remains to be studied.MethodsFDX1 expression was analyzed with The Cancer Genome Atlas (TCGA) database and Human Protein Atlas (HPA) database. Association between FDX1 expression and COAD prognosis was investigated via the Kaplan–Meier (KM) survival curve. The differentially expressed genes (DEGs) of FDX1 were screened with R packages and the PPI were constructed via STRING database. Cytoscape software was used to detect the most profound modules in the PPIs network. CancerSEA database was used to analyze the effect of FDX1 expression levels on different functional status of COAD cells. The relationship between FDX1 expression and immune infiltration of COAD was analyzed by TIMER2.0 database. The COAD patients with high expression of FDX1 by Western blot, and the levels of immune infiltration were measured by flow cytometry.ResultsFDX1 was low expressed in most cancers, such as BRCA, KICH, and COAD. The overall survival (OS) and disease-specific survival (DSS) of COAD with high FDX1 expression were better than that of the low expression group. GO-KEGG enrichment analysis revealed that FDX1 and its co-expressed genes played an important role in the pathogenesis of COAD. Moreover, FDX1 expression in COAD were positively associated with “quiescence” and “inflammation” but negatively correlated with “invasion”. FDX1 expression was positively correlated with infiltration levels of CD8+ T cells, NK cells, and neutrophils. Oppositely, FDX1 expression was negatively correlated with that of CD4+ T cells and cancer-associated fibroblasts (CAFs). Finally, 6 COAD patients with high expression of FDX1 were screened, and the proportion of CD8+ T cells in cancer tissues of these patients was significantly higher than that in paracancerous, while the CD4+ T cells presented the opposite pattern.ConclusionFDX1 plays a role in inducing cuproptosis and modulating tumor immunity, which could be considered as potential therapeutic targets in COAD.

Ferroptosis Inducers for Prostate Cancer Therapy.

Lipid peroxidation-driven iron-dependent ferroptosis is a regulated cell death mechanism implicated in numerous diseases, such as neurological diseases, kidney injury, ischemia, and tumors, including prostate cancer. The cellular mechanisms of ferroptosis are strongly associated with iron, reactive oxygen species and amino acid metabolic pathways. Several compounds, namely ferroptosis inducers, impact these pathways and trigger ferroptosis by i) inhibiting Xc - transporter system, ii) impairing GPX4 functions and iii) oxidizing iron and polyunsaturated phospholipids. Preclinical studies show that in combination with conventional anticancer drugs, ferroptosis inducers are effective in prostate cancer and in combating the progression towards the castration-resistant disease. This review overviews the mechanisms implicated in ferroptosis and discusses the findings achieved in prostate cancer.

Revisiting Regulated Cell Death Responses in Viral Infections.

The fate of a viral infection in the host begins with various types of cellular responses, such as abortive, productive, latent, and destructive infections. Apoptosis, necroptosis, and pyroptosis are the three major types of regulated cell death mechanisms that play critical roles in viral infection response. Cell shrinkage, nuclear condensation, bleb formation, and retained membrane integrity are all signs of osmotic imbalance-driven cytoplasmic swelling and early membrane damage in necroptosis and pyroptosis. Caspase-driven apoptotic cell demise is considered in many circumstances as an anti-inflammatory, and some pathogens hijack the cell death signaling routes to initiate a targeted attack against the host. In this review, the selected mechanisms by which viruses interfere with cell death were discussed in-depth and were illustrated by compiling the general principles and cellular signaling mechanisms of virus–host-specific molecule interactions.

Ferroptosis promotes T-cell activation-induced neurodegeneration in multiple sclerosis.

While many drugs are effective at reducing the relapse frequency of multiple sclerosis (MS), there is an unmet need for treatments that slow neurodegeneration resulting from secondary disease progression. The mechanism of neurodegeneration in MS has not yet been established. Here, we discovered a potential pathogenetic role of ferroptosis, an iron-dependent regulated cell death mechanism, in MS. We found that critical ferroptosis proteins (acyl-CoA synthetase long-chain family member 4, ACSL4) were altered in an existing genomic database of MS patients, and biochemical features of ferroptosis, including lipid reactive oxygen species (ROS) accumulation and mitochondrial shrinkage, were observed in the experimental autoimmune encephalitis (EAE) mouse model. Targeting ferroptosis with ferroptosis inhibitors or reducing ACSL4 expression improved the behavioral phenotypes of EAE mice, reduced neuroinflammation, and prevented neuronal death. We found that ferroptosis was an early event in EAE, which may promote T-cell activation through T-cell receptor (TCR) signaling in vitro and in vivo. These data indicate that ferroptosis may be a potential target for treating MS.

Novel Therapeutic Savior for Osteosarcoma: The Endorsement of Ferroptosis.

Ferroptosis has recently been discovered as an iron-dependent and non-apoptotic regulated mechanism of cell death. The induction of ferroptosis in tumor cells improves tumor treatment, making it a current research hotspot. Mechanistically, it starts by lipid peroxidation, iron accumulation, reactive oxygen species (ROS) production, and glutathione deprivation, highlighting novel treatment opportunities for many tumors and neurodegenerative disorders. Several tumor cell lines are resistant to ferroptosis inducers, even when the ferroptosis key enzyme glutathione peroxidase 4 (GPX4) is blocked, indicating that other important elements are also involved in this process. Ferroptosis-suppressor-protein 1 (FSP1) was discovered to be one of these elements in addition to a few others such as ferroptotic gatekeepers like GTP cyclohydrolase 1 (GCH1) and dihydroorotate dehydrogenase (DHODH). Osteosarcoma is the most common primary malignant bone tumor observed most frequently in children and adolescents. Several studies demonstrated that ferroptosis plays a critical role in the treatment of osteosarcoma, in particular drug-resistant osteosarcoma cells. We outlined four primary regulators involved in ferroptosis in this article, reviewed previously published studies of ferroptosis in osteosarcoma to provide covert insights about osteosarcoma treatment, and highlighted several critical issues to point out future research possibilities.

Development and Validation of a Necroptosis-Related Prognostic Model in Head and Neck Squamous Cell Carcinoma.

Necroptosis is a new regulated cell-death mechanism that plays a critical role in various cancers. However, few studies have considered necroptosis-related genes (NRGs) as prognostic indexes for cancer. As one of the most common cancers in the world, head and neck squamous cell carcinoma (HNSCC) lacks effective diagnostic strategies at present. Hence, a series of novel prognostic indexes are required to support clinical diagnosis. Recently, many studies have confirmed that necroptosis was a key regulated mechanism in HNSCC, but no systematic study has ever studied the correlation between necroptosis-related signatures and the prognosis of HNSCC. Thus, in the current study, we aimed to construct a risk model of necroptosis-related signatures for HNSCC. We acquired 159 NRGs from the Kyoto Encyclopedia of Genes and Genomes (KEGG) and compared them with samples of normal tissue downloaded from The Cancer Genome Atlas (TCGA), ultimately screening 38 differentially expressed NRGs (DE-NRGs). Then, by Cox regression analysis, we successfully identified 7 NRGs as prognostic factors. We next separated patients into high- and low-risk groups via the prognostic model consisting of 7 NRGs. Individuals in the high-risk group had much shorter overall survival (OS) times than their counterparts. Furthermore, using Cox regression analysis, we confirmed the necroptosis-related prognostic model to be an independent prognostic factor for HNSCC. Receiver operating characteristic (ROC) curve analysis proved the predictive ability of this model. Finally, Gene Expression Omnibus (GEO) data sets (GSE65858, GSE4163) were used as independent databases to verify the model's predictive ability, and similar results obtained from two data sets confirmed our conclusion. Collectively, in this study, we first referred to necroptosis-related signatures as an independent prognostic model for cancer via bioinformatics measures, and the necroptosis-related prognostic model we constructed could precisely forecast the OS time of patients with HNSCC. Utilizing the model may significantly improve the diagnostic rate and provide a series of new targets for treatment in the future.

Effects of Ferroptosis on the Metabolome in Cardiac Cells: The Role of Glutaminolysis.

Ferroptosis is a novel iron-dependent regulated cell death mechanism that affects cell metabolism; however, a detailed metabolomic analysis of ferroptotic cells is not yet available. Here, we elucidated the metabolome of H9c2 cardioblasts by gas chromatography-mass spectrometry during ferroptosis induced by RSL3, a GPX4 inhibitor, in the presence of ferrostatin-1 (a ferroptosis inhibitor), XJB-5-131 (a mitochondrial-targeted ROS scavenger), or TSM-1005-44 (a newly developed cellular ROS scavenger). Results demonstrated that RSL3 decreased the levels of amino acids involved in glutathione synthesis more than two-fold. In contrast, saturated fatty acids levels were markedly increased in RSL3-challenged cells, with no effects on unsaturated fatty acids. RSL3 significantly altered the levels of mitochondrial tricarboxylic acid cycle intermediates; isocitrate and 2-oxoglutarate were found to increase, whereas succinate was significantly decreased in RSL3-challenged cells. Ferrostatin-1, XJB-5-131, and TSM-1005-44 prevented RSL3-induced cell death and conserved the metabolomic profile of the cells. Since 2-oxoglutarate is involved in the regulation of ferroptosis, particularly through glutamine metabolism, we further assessed the role of glutaminolysis in ferroptosis in H9c2 cardioblasts. Genetic silencing of GLS1, which encodes the K-type mitochondrial glutaminase (glutaminase C), protected against ferroptosis in the early stage. In conclusion, our study demonstrates that RSL3-induced ferroptosis impairs the metabolome of H9c2 cardioblasts.

Nanoparticles for Ferroptosis Therapy in Cancer

Ferroptosis is a regulated cell death mechanism holding promise for anticancer therapy. Numerous small molecules inducing ferroptosis have been reported thus far. However, these compounds suffer from important drawbacks including poor solubility, systemic toxicity, and scarce tumor targeting ability that have limited their clinical success. The notion that nanoparticles inducing ferroptosis show better preclinical profiles compared to small molecules and overcome resistance to apoptosis has opened a new scenario for cancer treatment. Due to peculiar chemical-physical properties, nanoparticles can be loaded with anticancer drugs or decorated with tumor-selecting molecules. These features allow for drug combination treatment as well as tumor targeting. In the review, we summarize and discuss the available information concerning nanoparticles inducing ferroptosis endowed with different peculiarities and suitable for therapeutic purposes including nanoparticles for (i) antitumor drug delivery, (ii) tumor targeting, (iii) immunomodulation, and (iv) radiofrequency ablation, hyperthermia, and photodynamic therapy.

RIPK3 and AXL Expression Study in Primary Cutaneous Melanoma Unmasks AXL as Predictor of Sentinel Node Metastasis: A Pilot Study

Malignant melanoma (MM) is the most lethal skin cancer. AXL is a tyrosine kinase receptor involved in several oncogenic processes and might play a role in blocking necroptosis (a regulated cell death mechanism) in MM through the downregulation of the necroptotic-related driver RIPK3. The aim of this study was to evaluate the clinical impact of the expression of AXL and RIPK3 in 108 primary cutaneous MMs. Association between AXL and RIPK3 immunoreactivity and clinical–pathological variables, sentinel lymph node status, and tumor-infiltrating lymphocytes (TILs) was assessed. Immunoreaction in tumor cells was detected in 30 cases (28%; range, 5%–80%) and in 17 cases (16%; range, 5%–50%) for AXL and RIPK3, respectively. Metastases in the sentinel lymph nodes were detected in 14 out of 61 patients, and these were associated with AXL-positive immunoreactivity in the primary tumor (p < 0.0001). No association between AXL and TILs was found. RIPK3 immunoreactivity was not associated with any variables. A final logistic regression analysis showed Breslow and AXL-positive immunoreactivity as the stronger predictor for positive sentinel node status [area under the receiver operating characteristic curve (AUC) of 0.96]. AXL could be a potential new biomarker for MM risk assessment, and it deserves to be further investigated in larger studies.

Regulation of Cell Death Induced by Acetic Acid in Yeasts.

Acetic acid has long been considered a molecule of great interest in the yeast research field. It is mostly recognized as a by-product of alcoholic fermentation or as a product of the metabolism of acetic and lactic acid bacteria, as well as of lignocellulosic biomass pretreatment. High acetic acid levels are commonly associated with arrested fermentations or with utilization as vinegar in the food industry. Due to its obvious interest to industrial processes, research on the mechanisms underlying the impact of acetic acid in yeast cells has been increasing. In the past twenty years, a plethora of studies have addressed the intricate cascade of molecular events involved in cell death induced by acetic acid, which is now considered a model in the yeast regulated cell death field. As such, understanding how acetic acid modulates cellular functions brought about important knowledge on modulable targets not only in biotechnology but also in biomedicine. Here, we performed a comprehensive literature review to compile information from published studies performed with lethal concentrations of acetic acid, which shed light on regulated cell death mechanisms. We present an historical retrospective of research on this topic, first providing an overview of the cell death process induced by acetic acid, including functional and structural alterations, followed by an in-depth description of its pharmacological and genetic regulation. As the mechanistic understanding of regulated cell death is crucial both to design improved biomedical strategies and to develop more robust and resilient yeast strains for industrial applications, acetic acid-induced cell death remains a fruitful and open field of study.

The Role of Necroptosis: Biological Relevance and Its Involvement in Cancer.

Regulated cell death mechanisms are essential for the maintenance of cellular homeostasis. Evasion of cell death is one of the most important hallmarks of cancer. Necroptosis is a caspase independent form of regulated cell death, investigated as a novel therapeutic strategy to eradicate apoptosis resistant cancer cells. The process can be triggered by a variety of stimuli and is controlled by the activation of RIP kinases family as well as MLKL. The well-studied executor, RIPK1, is able to modulate key cellular events through the interaction with several proteins, acting as strategic crossroads of several molecular pathways. Little evidence is reported about its involvement in tumorigenesis. In this review, we summarize current studies on the biological relevance of necroptosis, its contradictory role in cancer and its function in cell fate control. Targeting necroptosis might be a novel therapeutic intervention strategy in anticancer therapies as a pharmacologically controllable event.

Autophagy Regulation and Photodynamic Therapy: Insights to Improve Outcomes of Cancer Treatment.

Cancer is considered an age-related disease that, over the next 10 years, will become the most prevalent health problem worldwide. Although cancer therapy has remarkably improved in the last few decades, novel treatment concepts are needed to defeat this disease. Photodynamic Therapy (PDT) signalize a pathway to treat and manage several types of cancer. Over the past three decades, new light sources and photosensitizers (PS) have been developed to be applied in PDT. Nevertheless, there is a lack of knowledge to explain the main biochemical routes needed to trigger regulated cell death mechanisms, affecting, considerably, the scope of the PDT. Although autophagy modulation is being raised as an interesting strategy to be used in cancer therapy, the main aspects referring to the autophagy role over cell succumbing PDT-photoinduced damage remain elusive. Several reports emphasize cytoprotective autophagy, as an ultimate attempt of cells to cope with the photo-induced stress and to survive. Moreover, other underlying molecular mechanisms that evoke PDT-resistance of tumor cells were considered. We reviewed the paradigm about the PDT-regulated cell death mechanisms that involve autophagic impairment or boosted activation. To comprise the autophagy-targeted PDT-protocols to treat cancer, it was underlined those that alleviate or intensify PDT-resistance of tumor cells. Thereby, this review provides insights into the mechanisms by which PDT can be used to modulate autophagy and emphasizes how this field represents a promising therapeutic strategy for cancer treatment.

Caspase-8 loss radiosensitizes head and neck squamous cell carcinoma to SMAC mimetic-induced necroptosis.

Caspase-8 (CASP8) is one of the most frequently mutated genes in head and neck squamous carcinomas (HNSCCs), and CASP8 mutations are associated with poor survival. The distribution of these mutations in HNSCCs suggests that they are likely to be inactivating. Inhibition of CASP8 has been reported to sensitize cancer cells to necroptosis, a regulated cell death mechanism. Here, we show that knockdown of CASP8 renders HNSCCs susceptible to necroptosis by a second mitochondria-derived activator of caspase (SMAC) mimetic, birinapant, in combination with pan-caspase inhibitors Z-VAD-FMK or emricasan and radiation. In a syngeneic mouse model of oral cancer, birinapant, particularly when combined with radiation, delayed tumor growth and enhanced survival under CASP8 loss. Exploration of molecular underpinnings of necroptosis sensitivity confirmed that the level of functional receptor-interacting serine/threonine protein kinase 3 (RIP3) determines susceptibility to this mode of death. Although an in vitro screen revealed that low RIP3 levels rendered many HNSCC cell lines resistant to necroptosis, patient tumors maintained RIP3 expression and should therefore remain sensitive. Collectively, these results suggest that targeting the necroptosis pathway with SMAC mimetics, especially in combination with radiation, may be relevant therapeutically in HNSCC with compromised CASP8 status, provided that RIP3 function is maintained.

Intracellular microRNA expression patterns influence cell death fates for both necrosis and apoptosis.

MicroRNAs (miRNAs) are small noncoding RNA molecules that interact with target mRNAs at specific sites to induce cleavage of the mRNA or inhibit translation. Such miRNAs play a vital role in gene expression and in several other biological processes, including cell death. We have studied the mechanisms regulating cell death (necrosis in original F28-7 cells and apoptosis in their variant F28-7-A cells) in the mouse mammary tumor cell line FM3A using the anticancer agent floxuridine (FUdR). We previously reported that inhibition of heat-shock protein 90 by the specific inhibitor geldanamycin (GA) in F28-7 cells causes a shift from necrosis to apoptosis. In this study, we investigated the intracellular miRNA expression profiles of FUdR-treated F28-7 cells (necrotic condition), GA plus FUdR-treated F28-7 cells (apoptotic condition), and FUdR-treated F28-7-A cells (apoptotic condition) through miRNA microarray analysis. In addition, we knocked down Dicer, a key molecule for the expression of mature miRNAs, in F28-7 cells to examine whether it modulates FUdR-induced cell death. Our analysis revealed that the miRNA expression patterns differ significantly between these cell death conditions. Furthermore, we identified miRNA candidates that regulate cell death. Knockdown of Dicer in FUdR-treated necrosis-fated cells caused a partial shift from necrosis to apoptosis. These findings suggest that modulation of miRNA expression patterns influences the decision of cell death fate toward necrosis or apoptosis. Our findings may serve as a basis for further study of the functions of miRNAs in cell death mechanisms.

Regulated cell death mechanisms and their crosstalk with the immune system 1

Regulated cell death mechanisms and their crosstalk with the immune system 1