Modulation of Ferroptosis by microRNAs in Human Cancer (original) (raw)
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miR-137 regulates ferroptosis by targeting glutamine transporter SLC1A5 in melanoma
Cell death and differentiation, 2018
Ferroptosis is a regulated form of cell death driven by small molecules or conditions that induce lipid-based reactive oxygen species (ROS) accumulation. This form of iron-dependent cell death is morphologically and genetically distinct from apoptosis, necroptosis, and autophagy. miRNAs are known to play crucial roles in diverse fundamental biological processes. However, to date no study has reported miRNA-mediated regulation of ferroptosis. Here we show that miR-137 negatively regulates ferroptosis by directly targeting glutamine transporter SLC1A5 in melanoma cells. Ectopic expression of miR-137 suppressed SLC1A5, resulting in decreased glutamine uptake and malondialdehyde (MDA) accumulation. Meanwhile, antagomir-mediated inactivation of endogenous miR-137 increased the sensitivity of melanoma cells to erastin- and RSL3-induced ferroptosis. Importantly, knockdown of miR-137 increased the antitumor activity of erastin by enhancing ferroptosis both in vitro and in vivo. Collectively...
Linking Cancer Metabolic Dysfunction and Genetic Instability through the Lens of Iron Metabolism
Cancers, 2019
Iron (Fe) is an essential element that plays a fundamental role in a wide range of cellular functions, including cellular proliferation, DNA synthesis, as well as DNA damage and repair. Because of these connections, iron has been strongly implicated in cancer development. Cancer cells frequently have changes in the expression of iron regulatory proteins. For example, cancer cells frequently upregulate transferrin (increasing uptake of iron) and down regulate ferroportin (decreasing efflux of intracellular iron). These changes increase the steady-state level of intracellular redox active iron, known as the labile iron pool (LIP). The LIP typically contains approximately 2% intracellular iron, which primarily exists as ferrous iron (Fe2+). The LIP can readily contribute to oxidative distress within the cell through Fe2+-dioxygen and Fenton chemistries, generating the highly reactive hydroxyl radical (HO•). Due to the reactive nature of the LIP, it can contribute to increased DNA damag...
Close interactions between lncRNAs, lipid metabolism and ferroptosis in cancer
International Journal of Biological Sciences
Abnormal lipid metabolism including synthesis, uptake, modification, degradation and transport has been considered a hallmark of malignant tumors and contributes to the supply of substances and energy for rapid cell growth. Meanwhile, abnormal lipid metabolism is also associated with lipid peroxidation, which plays an important role in a newly discovered type of regulated cell death termed ferroptosis. Long noncoding RNAs (lncRNAs) have been proven to be associated with the occurrence and progression of cancer. Growing evidence indicates that lncRNAs are key regulators of abnormal lipid metabolism and ferroptosis in cancer. In this review, we mainly summarized the mechanism by which lncRNAs regulate aberrant lipid metabolism in cancer, illustrated that lipid metabolism can also influence the expression of lncRNAs, and discussed the mechanism by which lncRNAs affect ferroptosis. A comprehensive understanding of the interactions between lncRNAs, lipid metabolism and ferroptosis could help us to develop novel strategies for precise cancer treatment in the future.
2022
Medulloblastoma (MB), the most common malignant pediatric brain tumor and a leading cause of childhood mortality, is stratified into four primary subgroups, WNT (wingless), SHH (sonic hedgehog), group 3, and group 4. Patients with group 3 tumors have the poorest prognosis. Loss of 17p13.3, which houses the tumor suppressor gene miR-1253, is a frequent high-risk feature of group 3 tumors.. In this study, we show that miR-1253 levels can disrupt iron homeostasis, induce oxidative stress and lipid peroxidation, triggering an iron-mediated form of cell death called ferroptosis. In silico and in vitro analyses of group 3 tumors revealed deregulation of ABCB7, a mitochondrial iron transporter and target of miR-1253, and GPX4, a critical regulator of ferroptosis. Restoration of miR-1253 levels in group 3 cell lines resulted in downregulation of ABCB7 and GPX4, consequently increasing cytosolic and mitochondrial labile iron pools, reducing glutathione levels, in turn, resulting in mitochond...
miRNAs, oxidative stress, and cancer: A comprehensive and updated review
Journal of Cellular Physiology, 2020
Oxidative stress refers to elevated levels of intracellular reactive oxygen species (ROS). ROS homeostasis functions as a signaling pathway for normal cell survival and appropriate cell signaling. Chronic inflammation induced by imbalanced levels of ROS contributes to many diseases and different types of cancer. ROS can alter the expression of oncogenes and tumor suppressor genes through epigenetic modifications, transcription factors, and non-coding RNAs. MicroRNAs (miRNAs) are small non-coding RNAs that play a key role in most biological pathways. Each miRNA regulates hundreds of target genes by inhibiting protein translation and/or promoting messenger RNA degradation. In normal conditions, miRNAs play a physiological role in cell proliferation, differentiation, and apoptosis. However, different factors that can dysregulate cell signaling and cellular homeostasis can also affect miRNA expression. The alteration of miRNA expression can work against disturbing factors or mediate their effects. Oxidative stress is one of these factors. Considering the complex interplay between ROS level and miRNA regulation and both of these with cancer development, we review the role of miRNAs in cancer, focusing on their function in oxidative stress.
Molecules
Iron is a crucial element required for the proper functioning of the body. For instance, hemoglobin is the vital component in the blood that delivers oxygen to various parts of the body. The heme protein present in hemoglobin comprises iron in the form of a ferrous state which regulates oxygen delivery. Excess iron in the body is stored as ferritin and would be utilized under iron-deficient conditions. Surprisingly, cancer cells as well as cancer stem cells have elevated ferritin levels suggesting that iron plays a vital role in protecting these cells. However, apart from the cytoprotective role iron also has the potential to induce cell death via ferroptosis which is a non-apoptotic cell death dependent on iron reserves. Apoptosis a caspase-dependent cell death mechanism is effective on cancer cells however little is known about its impact on cancer stem cell death. This paper focuses on the molecular characteristics of apoptosis and ferroptosis and the importance of switching to f...
Cell Death Discovery, 2021
Colorectal cancer (CRC) is a common tumor that harms human health with a high recurrence rate. It has been reported that the expression of microRNA-539 (miR-539) is low in several types of cancer, including CRC. Tumor necrosis factor (TNF)-α-induced protein 8 (TNFAIP8/TIPE) is highly expressed in CRC and promotes the proliferation, migration and angiogenesis of CRC. However, the relationship between miR-539 and TIPE and the mechanisms by which they regulate the proliferation of CRC remain to be explored. We aimed to investigate the functions and mechanisms of miR-539 in CRC proliferation. Functionally, miR-539 can bind to and regulate the expression of TIPE, and miR-539 activates SAPK/JNK to downregulate the expression of glutathione peroxidase 4 (GPX4) and promote ferroptosis. Our data reveal the novel role of miR-539 in regulating ferroptosis in CRC via activation of the SAPK/JNK axis, providing new insight into the mechanism of abnormal proliferation in CRC and a novel potential ...
Mechanistic insights into the role of microRNAs in cancer: Influence of nutrient crosstalk
2012
A plethora of studies have described the disruption of key cellular regulatory mechanisms involving non-coding RNAs, specifically microRNAs (miRNA) from the let-7 family, the miR-17 family, miR-21, miR-143, and the miR-200 family, which contribute to aberrant signaling and tumor formation. Certain environmental factors, such as bioactive dietary agents, e.g., folate, curcumin, polyunsaturated fatty acids, are also thought to impact the progression and severity of cancer. In terms of the chemoprotective mechanisms of action, these bioactive dietary agents appear to act, in part, by modulating tissue levels of miR-16, miR-17 family, miR-26b, miR-106b, and miR-200 family miRNAs and their target genes. However, the mechanisms of nutrient action are not yet fully understood. Therefore, additional characterization of the putative underlying mechanisms is needed to further our understanding of the biology, early diagnosis, prevention, and the treatment of cancer. For the purpose of elucidating the epigenetic landscape of cancer, this review will summarize the key findings from recent studies detailing the effect of bioactive dietary agents on miRNA regulation in cancer.
Ferroptosis: A New Road towards Cancer Management
Molecules
Ferroptosis is a recently described programmed cell death mechanism that is characterized by the buildup of iron (Fe)-dependent lipid peroxides in cells and is morphologically, biochemically, and genetically distinct from other forms of cell death, having emerged to play an important role in cancer biology. Ferroptosis has significant importance during cancer treatment because of the combination of factors, including suppression of the glutathione peroxidase 4 (Gpx4), cysteine deficiency, and arachidonoyl (AA) peroxidation, which cause cells to undergo ferroptosis. However, the physiological significance of ferroptosis throughout development is still not fully understood. This current review is focused on the factors and molecular mechanisms with the diagrammatic illustrations of ferroptosis that have a role in the initiation and sensitivity of ferroptosis in various malignancies. This knowledge will open a new road for research in oncology and cancer management.