scholarly journals 7-Dehydrocholesterol is an endogenous suppressor of ferroptosis

2021 ◽  
Author(s):  
Jose Pedro Friedmann Angeli ◽  
Florencio Porto Freitas ◽  
Palina Nepachalovich ◽  
Lohans Puentes ◽  
Omkar Zilka ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Cancer Cells ◽  
Survival Function ◽  
Peroxyl Radicals ◽  
Metabolic Adaptation ◽  
Compelling Evidence ◽  
Intrinsic Mechanism ◽  
A Cell ◽  
Developing Neurons

Abstract Ferroptosis is a form of cell death that has received considerable attention not only as a means to eradicate defined tumour entities but also because it provides unforeseen insights into the metabolic adaptation exploited by tumours to counteract phospholipid oxidation. Here, we identify a pro-ferroptotic activity of 7-dehydrocholesterol reductase (DHCR7) and an unexpected pro-survival function of its substrate, 7-dehydrocholesterol (7-DHC). Although previous studies suggested that high levels of 7-DHC are cytotoxic to developing neurons and favour lipid peroxidation, we now demonstrate that 7-DHC accumulation confers a robust pro-survival function in cancer cells. 7-DHC, due to its far superior reactivity towards peroxyl radicals, is shown here to effectively shield (phospho)lipids from autoxidation and subsequent fragmentation. We further demonstrate in a subset of ferroptosis-sensitive Burkitt lymphomas - where DHCR7 mutations have been reported - that the accumulation of 7-DHC is sufficient to suppress the basal sensitivity of cells toward ferroptosis, thereby translating into an unexpected growth advantage. Conclusively, our findings provide compelling evidence of a yet-unrecognised anti-ferroptotic activity of 7-DHC as a cell-intrinsic mechanism that could be exploited by cancer cells to escape ferroptosis.

scholarly journals Drugs Repurposed as Antiferroptosis Agents Suppress Organ Damage, Including AKI, by Functioning as Lipid Peroxyl Radical Scavengers

2019 ◽  
Vol 31 (2) ◽  
pp. 280-296 ◽  
Author(s):  
Eikan Mishima ◽  
Emiko Sato ◽  
Junya Ito ◽  
Ken-ichi Yamada ◽  
Chitose Suzuki ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Cytochrome P450 ◽  
Liver Injury ◽  
Peroxyl Radical ◽  
Organ Damage ◽  
Peroxyl Radicals ◽  
Radical Scavengers ◽  
Lipid Peroxyl Radicals ◽  
Elevated Lipid

BackgroundFerroptosis, nonapoptotic cell death mediated by free radical reactions and driven by the oxidative degradation of lipids, is a therapeutic target because of its role in organ damage, including AKI. Ferroptosis-causing radicals that are targeted by ferroptosis suppressors have not been unequivocally identified. Because certain cytochrome P450 substrate drugs can prevent lipid peroxidation via obscure mechanisms, we evaluated their antiferroptotic potential and used them to identify ferroptosis-causing radicals.MethodsUsing a cell-based assay, we screened cytochrome P450 substrate compounds to identify drugs with antiferroptotic activity and investigated the underlying mechanism. To evaluate radical-scavenging activity, we used electron paramagnetic resonance–spin trapping methods and a fluorescence probe for lipid radicals, NBD-Pen, that we had developed. We then assessed the therapeutic potency of these drugs in mouse models of cisplatin-induced AKI and LPS/galactosamine-induced liver injury.ResultsWe identified various US Food and Drug Administration–approved drugs and hormones that have antiferroptotic properties, including rifampicin, promethazine, omeprazole, indole-3-carbinol, carvedilol, propranolol, estradiol, and thyroid hormones. The antiferroptotic drug effects were closely associated with the scavenging of lipid peroxyl radicals but not significantly related to interactions with other radicals. The elevated lipid peroxyl radical levels were associated with ferroptosis onset, and known ferroptosis suppressors, such as ferrostatin-1, also functioned as lipid peroxyl radical scavengers. The drugs exerted antiferroptotic activities in various cell types, including tubules, podocytes, and renal fibroblasts. Moreover, in mice, the drugs ameliorated AKI and liver injury, with suppression of tissue lipid peroxidation and decreased cell death.ConclusionsAlthough elevated lipid peroxyl radical levels can trigger ferroptosis onset, some drugs that scavenge lipid peroxyl radicals can help control ferroptosis-related disorders, including AKI.

scholarly journals Methylseleninic Acid Induces Lipid Peroxidation and Radiation Sensitivity in Head and Neck Cancer Cells

2019 ◽  
Vol 20 (1) ◽  
pp. 225 ◽  
Author(s):  
John T. Lafin ◽  
Ehab H. Sarsour ◽  
Amanda L. Kalen ◽  
Brett A. Wagner ◽  
Garry R. Buettner ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Head And Neck ◽  
Cancer Cells ◽  
Clonogenic Assay ◽  
Radiation Sensitivity ◽  
Selenium Compounds ◽  
Ferric Thiocyanate ◽  
Methylseleninic Acid ◽  
Intracellular Glutathione ◽  
A Cell

Combination radiation and chemotherapy are commonly used to treat locoregionally advanced head and neck squamous cell carcinoma (HNSCC). Aggressive dosing of these therapies is significantly hampered by side effects due to normal tissue toxicity. Selenium represents an adjuvant that selectively sensitizes cancer cells to these treatments modalities, potentially by inducing lipid peroxidation (LPO). This study investigated whether one such selenium compound, methylseleninic acid (MSA), induces LPO and radiation sensitivity in HNSCC cells. Results from 4,4-difluoro-4-bora-3a,4a-diaza-S-indacene (BODIPY) C11 oxidation and ferric thiocyanate assays revealed that MSA induced LPO in cells rapidly and persistently. Propidium iodide (PI) exclusion assay found that MSA was more toxic to cancer cells than other related selenium compounds; this toxicity was abrogated by treatment with α-tocopherol, an LPO inhibitor. MSA exhibited no toxicity to normal fibroblasts at similar doses. MSA also sensitized HNSCC cells to radiation as determined by clonogenic assay. Intracellular glutathione in cancer cells was depleted following MSA treatment, and supplementation of the intracellular glutathione pool with N-acetylcysteine sensitized cells to MSA. The addition of MSA to a cell-free solution of glutathione resulted in an increase in oxygen consumption, which was abrogated by catalase, suggesting the formation of H2O2. Results from this study identify MSA as an inducer of LPO, and reveal its capability to sensitize HNSCC to radiation. MSA may represent a potent adjuvant to radiation therapy in HNSCC.

scholarly journals Human Satellite III long non-coding RNA imparts survival benefits to cancer cells

2021 ◽  
Author(s):  
Manjima Chatterjee ◽  
Sonali Sengupta
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Heat Shock ◽  
Human Chromosome ◽  
Cell Survival ◽  
Cancer Cells ◽  
Survival Function ◽  
Human Cancers ◽  
Satellite Rnas ◽  
Non Coding Rnas

ABSTRACTLong non-coding RNAs are heterogeneous group of transcripts that lack coding potential and have crucial roles in gene regulations. Recent days have seen an increasing association of non-coding RNAs with human diseases, especially cancers. Satellite III (SatIII) lncRNAs are transcribed from pericentromeric heterochromatic region of the human chromosome. Though transcriptionally silent in normal conditions, SatIII is actively transcribed under condition of stress, mainly heat shock. SatII repeat, another component of pericentromeric region of human chromosome, has been associated with wide variety of epithelial cancer. Overexpression of Satellite RNAs induces breast cancer in mice. Though much is known about Satellite RNAs, which includes alpha satellites and SatII repeats, however little is known about SatIII in human cancers. Hence we directed our study to understand the role of human Satellite III repeats in cancerous conditions. In the present study, we show that colon and breast cancer cells transcribe SatIII independent of heat shock, in an HSF1-independent manner. Our study also reveals that, overexpression of SatIII RNA favours cancer cell survival by overriding chemo drug-induced cell death. Knockdown of SatIII sensitizes cells towards chemotherapeutic drugs. SatIII transcript knockdown restores the expression of p53 protein, which in turn facilitates cell death. Heat shock however helps SatIII to continue with its pro-cell survival function. Our results, therefore suggest SatIII to be an important regulator of human cancers. Induction of SatIII is not only a response to the oncogenic stress but also facilitates cancer progression by a distinct pathway that is different from heat stress pathway.

scholarly journals Opportunities for Ferroptosis in Cancer Therapy

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 986
Author(s):  
Kenji M. Fujihara ◽  
Bonnie Z. Zhang ◽  
Nicholas J. Clemons
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Cancer Therapy ◽  
Cancer Cells ◽  
Therapeutic Strategy ◽  
Molecular Mechanisms ◽  
Apoptotic Cell ◽  
Cancer Therapeutics ◽  
Therapeutic Window ◽  
Anti Cancer

A critical hallmark of cancer cells is their ability to evade programmed apoptotic cell death. Consequently, resistance to anti-cancer therapeutics is a hurdle often observed in the clinic. Ferroptosis, a non-apoptotic form of cell death distinguished by toxic lipid peroxidation and iron accumulation, has garnered substantial attention as an alternative therapeutic strategy to selectively destroy tumours. Although there is a plethora of research outlining the molecular mechanisms of ferroptosis, these findings are yet to be translated into clinical compounds inducing ferroptosis. In this perspective, we elaborate on how ferroptosis can be leveraged in the clinic. We discuss a therapeutic window for compounds inducing ferroptosis, the subset of tumour types that are most sensitive to ferroptosis, conventional therapeutics that induce ferroptosis, and potential strategies for lowering the threshold for ferroptosis.

Requirement of p38 MAPK for a cell-death pathway triggered by vorinostat in MDA-MB-231 human breast cancer cells

2012 ◽  
Vol 315 (2) ◽  
pp. 112-121 ◽  
Author(s):  
Norihisa Uehara ◽  
Sayaka Kanematsu ◽  
Hisanori Miki ◽  
Katsuhiko Yoshizawa ◽  
Airo Tsubura
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
P38 Mapk ◽  
Human Breast Cancer ◽  
Breast Cancer Cells ◽  
Human Breast Cancer Cells ◽  
Human Breast ◽  
Cell Death Pathway ◽  
A Cell

scholarly journals A redox-dependent mechanism for AMPK dysregulation interrupts metabolic adaptation of cancer under glucose deprivation

2021 ◽  
Author(s):  
Younghwan Lee ◽  
Yoko Itahana ◽  
Choon Chen Ong ◽  
Koji Itahana
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Cell Lines ◽  
Aerobic Glycolysis ◽  
Glucose Deprivation ◽  
Redox System ◽  
Metabolic Adaptation ◽  
Acid Oxidation ◽  
Cancer Type ◽  
Metabolic Switch

AbstractAccelerated aerobic glycolysis is a distinctive metabolic property of cancer cells that confers dependency on glucose for survival. However, the selective therapeutic targeting of this vulnerability has yielded mixed results owing to the different sensitivities of each cancer type to glucose removal and lack of insight into the underlying mechanisms of glucose deprivation-induced cell death.Here, we screened multiple cell lines to determine their sensitivities to glucose deprivation and found that the cell lines most sensitive to glucose deprivation failed to activate AMPK, a major regulator of metabolic adaptation, resulting in metabolic catastrophe.Notably, glucose deprivation-induced AMPK dysregulation and rapid cell death were observed only in cancer cell lines with high expression of cystine/glutamate antiporter xCT. While this phenomenon was prevented by pharmacological or genetic inhibition of xCT, overexpression of xCT sensitized resistant cancer cells to glucose deprivation. We found that cystine uptake and glutamate export through xCT under glucose deprivation contributes to rapid NADPH depletion, leading to the collapse of the redox system, which subsequently inactivates AMPK by inhibitory oxidation and phosphorylation. This AMPK dysregulation caused a failure of metabolic switch to fatty acid oxidation upon glucose deprivation, resulting in mitochondrial dysfunction and cell death.Taken together, these findings suggest a novel cross-talk between the metabolic and signal transduction and reveal a metabolic vulnerability in xCT-high expressing cancer cells to glucose deprivation and provide a rationale for targeting glucose metabolism in these cancer cells.

scholarly journals Ferroptosis: The Silver Lining of Cancer Therapy

2021 ◽  
Vol 9 ◽  
Author(s):  
Zhengming Tang ◽  
Zhijie Huang ◽  
Yisheng Huang ◽  
Yuanxin Chen ◽  
Mingshu Huang ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Cancer Therapy ◽  
Cancer Cells ◽  
Future Perspectives ◽  
Major Focus ◽  
Therapeutic Modalities ◽  
Regulated Cell Death ◽  
Physiological Properties ◽  
Silver Lining

Regulatory cell death has been a major focus area of cancer therapy research to improve conventional clinical cancer treatment (e.g. chemotherapy and radiotherapy). Ferroptosis, a novel form of regulated cell death mediated by iron-dependent lipid peroxidation, has been receiving increasing attention since its discovery in 2012. Owing to the highly iron-dependent physiological properties of cancer cells, targeting ferroptosis is a promising approach in cancer therapy. In this review, we summarised the characteristics of ferroptotic cells, associated mechanisms of ferroptosis occurrence and regulation and application of the ferroptotic pathway in cancer therapy, including the use of ferroptosis in combination with other therapeutic modalities. In addition, we presented the challenges of using ferroptosis in cancer therapy and future perspectives that may provide a basis for further research.

An Aptamer Bio-barCode (ABC) assay using SPR, RNase H, and probes with RNA and gold-nanorods for anti-cancer drug screening

The Analyst ◽  
2017 ◽  
Vol 142 (19) ◽  
pp. 3579-3587 ◽  
Author(s):  
Jacky Fong-Chuen Loo ◽  
Chengbin Yang ◽  
Hing Lun Tsang ◽  
Pui Man Lau ◽  
Ken-Tye Yong ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Gold Nanorods ◽  
Drug Screening ◽  
Rnase H ◽  
Cancer Drug ◽  
Next Generation ◽  
Anti Cancer ◽  
A Cell

We have developed a next generation aptamer-based bio-barcode (ABC) assay to detect cytochrome-c (Cyto-c), a cell death marker released from cancer cells, for anti-cancer drug screening.

scholarly journals Non-apoptotic function of caspase-8 confers prostate cancer enzalutamide resistance via NF-κB activation

2021 ◽  
Vol 12 (9) ◽  
Author(s):  
Jia Xia ◽  
Jiahui Zhang ◽  
Liangzhe Wang ◽  
Hailong Liu ◽  
Jie Wang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Survival Function ◽  
Caspase 8 ◽  
Prostate Cancer Cells ◽  
Survival Signaling ◽  
Consequent Increase ◽  
Worse Prognosis

AbstractCaspase-8 is a unique member of caspases with a dual role in cell death and survival. Caspase-8 expression is often lost in some tumors, but increased in others, indicating a potential pro-survival function in cancer. By analyzing transcriptome of enzalutamide-resistant prostate cancer cells, we found that resistance was conferred by a mild caspase-8 upregulation that in turn led to NF-κB activation and the subsequent upregulation of the downstream IL-8. Mechanistically, we found that the pro-survival and enzalutamide-resistance-promoting features of caspase-8 were independent of its proteolytic activity, using a catalytically-inactive caspase-8 mutant. We further demonstrated that caspase-8 pro-apoptotic function was inhibited via cFLIP binding. Moreover, high caspase-8 expression was correlated with a worse prognosis in prostate cancer patients. Collectively, our work demonstrates that enzalutamide-resistance is mediated by caspase-8 upregulation and the consequent increase in NF-κB/IL-8 mediated survival signaling, highlighting caspase-8 and NF-κB as potential therapeutic targets to overcome enzalutamide-resistance in CRPC.

scholarly journals Nutrient Availability Alters the Effect of Autophagy on Sulindac Sulfide-Induced Colon Cancer Cell Apoptosis

2012 ◽  
Vol 2012 ◽  
pp. 1-9
Author(s):  
Shiun-Kwei Chiou ◽  
Neil Hoa ◽  
Lisheng Ge ◽  
Martin R. Jadus
Keyword(s):  
Colon Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Colon Cancer Cells ◽  
Autophagy Induction ◽  
A Cell ◽  
Sulindac Sulfide ◽  
Induced Apoptosis ◽  
Apoptosis Inhibitor ◽  
Ht 29

Autophagy is a catabolic process by which a cell degrades its intracellular materials to replenish itself. Induction of autophagy under various cellular stress stimuli can lead to either cell survival or cell death via apoptotic and/or autophagic (nonapoptotic) pathways. The NSAID sulindac sulfide induces apoptosis in colon cancer cells. Here, we show that inhibition of autophagy under serum-deprived conditions resulted in significant reductions of sulindac sulfide-induced apoptosis in HT-29 colon cancer cells. In contrast, inhibition of autophagy under conditions where serum is available significantly increased sulindac sulfide-induced apoptosis in HT-29 cells. We previously showed that the apoptosis inhibitor, survivin, plays a role in regulating NSAID-induced apoptosis and autophagic cell death. Here, we show that survivin protein half-life is increased in the presence of autophagy inhibitors under serum-deprived conditions, but not under conditions when serum is available. Thus, the increased levels of survivin may be a factor contributing to inhibition of sulindac sulfide-induced apoptosis under serum-deprived conditions. These results suggest that whether a cell lives or dies due to autophagy induction depends on the balance of factors that regulate both autophagic and apoptotic processes.

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