Abstract:Ferroptosis is a new form of programmed cell death with characteristic accumulation of reactive oxygen species (ROS) resulting from iron accumulation and lipid peroxidation. Ferroptosis is involved in many diseases, including cancer, and induction of ferroptosis has shown attractive antitumour activities. In this review, we summarize recent findings on the regulatory mechanisms of key regulators of ferroptosis, including the catalytic subunit solute carrier family 7 member 11 (SLC7A11), the glutathione peroxid… Show more
“…As diminished levels of NCOA4 dampen ferritinophagy ferritins, especially FTMT, increases with the ability to interfere with RSL-3-induced ferroptosis. Since ferroptosis is discussed as a strategy for tumor therapy and hypoxia appears as a cardinal sign of many tumors, we intended to explore the role of ferritins and NCOA4 in ferroptosis of HT1080 fibrosarcoma cells [ [42] , [43] , [44] ]. Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Induction of ferroptosis by pharmacological interference either by inhibition of the X - -transporter or GPX4 is an emerging concept for cancer therapy [ 43 , 44 ]. For stromal cells, i.e.…”
Cellular iron, at the physiological level, is essential to maintain several metabolic pathways, while an excess of free iron may cause oxidative damage and/or provoke cell death. Consequently, iron homeostasis has to be tightly controlled. Under hypoxia these regulatory mechanisms for human macrophages are not well understood. Hypoxic primary human macrophages reduced intracellular free iron and increased ferritin expression, including mitochondrial ferritin (FTMT), to store iron. In parallel, nuclear receptor coactivator 4 (NCOA4), a master regulator of ferritinophagy, decreased and was proven to directly regulate FTMT expression. Reduced NCOA4 expression resulted from a lower rate of hypoxic NCOA4 transcription combined with a micro RNA 6862-5p-dependent degradation of NCOA4 mRNA, the latter being regulated by c-jun N-terminal kinase (JNK). Pharmacological inhibition of JNK under hypoxia increased NCOA4 and prevented FTMT induction. FTMT and ferritin heavy chain (FTH) cooperated to protect macrophages from RSL-3-induced ferroptosis under hypoxia as this form of cell death is linked to iron metabolism. In contrast, in HT1080 fibrosarcome cells, which are sensitive to ferroptosis, NCOA4 and FTMT are not regulated. Our study helps to understand mechanisms of hypoxic FTMT regulation and to link ferritinophagy and macrophage sensitivity to ferroptosis.
“…As diminished levels of NCOA4 dampen ferritinophagy ferritins, especially FTMT, increases with the ability to interfere with RSL-3-induced ferroptosis. Since ferroptosis is discussed as a strategy for tumor therapy and hypoxia appears as a cardinal sign of many tumors, we intended to explore the role of ferritins and NCOA4 in ferroptosis of HT1080 fibrosarcoma cells [ [42] , [43] , [44] ]. Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Induction of ferroptosis by pharmacological interference either by inhibition of the X - -transporter or GPX4 is an emerging concept for cancer therapy [ 43 , 44 ]. For stromal cells, i.e.…”
Cellular iron, at the physiological level, is essential to maintain several metabolic pathways, while an excess of free iron may cause oxidative damage and/or provoke cell death. Consequently, iron homeostasis has to be tightly controlled. Under hypoxia these regulatory mechanisms for human macrophages are not well understood. Hypoxic primary human macrophages reduced intracellular free iron and increased ferritin expression, including mitochondrial ferritin (FTMT), to store iron. In parallel, nuclear receptor coactivator 4 (NCOA4), a master regulator of ferritinophagy, decreased and was proven to directly regulate FTMT expression. Reduced NCOA4 expression resulted from a lower rate of hypoxic NCOA4 transcription combined with a micro RNA 6862-5p-dependent degradation of NCOA4 mRNA, the latter being regulated by c-jun N-terminal kinase (JNK). Pharmacological inhibition of JNK under hypoxia increased NCOA4 and prevented FTMT induction. FTMT and ferritin heavy chain (FTH) cooperated to protect macrophages from RSL-3-induced ferroptosis under hypoxia as this form of cell death is linked to iron metabolism. In contrast, in HT1080 fibrosarcome cells, which are sensitive to ferroptosis, NCOA4 and FTMT are not regulated. Our study helps to understand mechanisms of hypoxic FTMT regulation and to link ferritinophagy and macrophage sensitivity to ferroptosis.
“…Therefore, the suppression of GPX4 or FSP1 is also able to induce ferroptosis effectively, without affecting the normal cellular levels of cysteine and GSH [ [3] , [4] , [5] ]. In recent years, the position of ferroptosis in different diseases, such as carcinogenesis [ 6 , 7 ], Alzheimer's disease [ 8 ], brain injury [ 9 , 10 ], lung injury [ 11 ] and ischemia-reperfusion injury [ 10 ], has been investigated by different groups. Especially for cancer research and therapy, scientists find that some types of cancer cells are sensitive to ferroptosis inducers, even though they are resistant to the traditional chemotherapy [ 12 ].…”
Transcription factor nuclear factor-erythroid 2-like 2 (NRF2) mainly regulates cellular antioxidant response, redox homeostasis and metabolic balance. Our previous study illustrated the translational significance of NRF2-mediated transcriptional repression, and the transcription of
FOCAD
gene might be negatively regulated by NRF2. However, the detailed mechanism and the related significance remain unclear. In this study, we mainly explored the effect of NRF2-FOCAD signaling pathway on ferroptosis regulation in human non-small-cell lung carcinoma (NSCLC) model. Our results confirmed the negative regulation relationship between NRF2 and FOCAD, which was dependent on NRF2-Replication Protein A1 (RPA1)-Antioxidant Response Elements (ARE) complex. In addition, FOCAD promoted the activity of focal adhesion kinase (FAK), which further enhanced the sensitivity of NSCLC cells to cysteine deprivation-induced ferroptosis via promoting the tricarboxylic acid (TCA) cycle and the activity of Complex I in mitochondrial electron transport chain (ETC). However, FOCAD didn't affect GPX4 inhibition-induced ferroptosis. Moreover, the treatment with the combination of NRF2 inhibitor (brusatol) and erastin showed better therapeutic action against NSCLC
in vitro
and
in vivo
than single treatment, and the improved therapeutic function partially depended on the activation of FOCAD-FAK signal. Taken together, our study indicates the close association of NRF2-FOCAD-FAK signaling pathway with cysteine deprivation-induced ferroptosis, and elucidates a novel insight into the ferroptosis-based therapeutic approach for the patients with NSCLC.
“…Knockdown of SNHG1 inhibited cell proliferation and promoted apoptosis. In another study, in which down-regulation of lncRNA LINC00702 inhibited Wnt signal activity in malignant meningioma, induction of apoptosis and decreased meningioma cell proliferation were observed ( 78 ). Unfortunately, there are few studies of the inhibition of apoptosis via the Wnt signaling pathway in meningioma.…”
Section: Molecular Mechanisms Of Change In Biological Behaviormentioning
Meningioma is the most common tumor of the central nervous system, most of which is benign. Even after complete resection, a high rate of recurrence of meningioma is observed. From in-depth study of its pathogenesis, it has been found that a number of chromosomal variations and abnormal molecular signals are closely related to the occurrence and development of malignancy in meningioma, which may provide the theoretical basis and potential direction for accurate and targeted treatment. We have reviewed advances in chromosomal variations and molecular mechanisms involved in the progression of meningioma, and have highlighted the association with malignant biological behavior including cell proliferation, angiogenesis, increased invasiveness, and inhibition of apoptosis. In addition, the chemotherapy of meningioma is summarized and discussed.
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