Glutathione peroxidase 4 (GPX4) utilizes glutathione (GSH) to detoxify lipid peroxidation and plays an essential role in inhibiting ferroptosis. As a selenoprotein, GPX4 protein synthesis is highly ...inefficient and energetically costly. How cells coordinate GPX4 synthesis with nutrient availability remains unclear. In this study, we perform integrated proteomic and functional analyses to reveal that SLC7A11-mediated cystine uptake promotes not only GSH synthesis, but also GPX4 protein synthesis. Mechanistically, we find that cyst(e)ine activates mechanistic/mammalian target of rapamycin complex 1 (mTORC1) and promotes GPX4 protein synthesis at least partly through the Rag-mTORC1-4EBP signaling axis. We show that pharmacologic inhibition of mTORC1 decreases GPX4 protein levels, sensitizes cancer cells to ferroptosis, and synergizes with ferroptosis inducers to suppress patient-derived xenograft tumor growth in vivo. Together, our results reveal a regulatory mechanism to coordinate GPX4 protein synthesis with cyst(e)ine availability and suggest using combinatorial therapy of mTORC1 inhibitors and ferroptosis inducers in cancer treatment.
Long non-coding RNAs (lncRNAs) have emerged as critical regulators in various cellular processes. However, the potential involvement of lncRNAs in kinase signalling remains largely unknown. ...AMP-activated protein kinase (AMPK) acts as a critical sensor of cellular energy status. Here we show that the lncRNA NBR2 (neighbour of BRCA1 gene 2) is induced by the LKB1-AMPK pathway under energy stress. On energy stress, NBR2 in turn interacts with AMPK and promotes AMPK kinase activity, thus forming a feed-forward loop to potentiate AMPK activation during energy stress. Depletion of NBR2 attenuates energy-stress-induced AMPK activation, resulting in unchecked cell cycling, altered apoptosis/autophagy response, and increased tumour development in vivo. NBR2 is downregulated and its low expression correlates with poor clinical outcomes in some human cancers. Together, the results of our study uncover a mechanism coupling lncRNAs with metabolic stress response, and provides a broad framework to understand further the regulation of kinase signalling by lncRNAs.
SLC7A11-mediated cystine uptake is critical for maintaining redox balance and cell survival. Here we show that this comes at a significant cost for cancer cells with high levels of SLC7A11. Actively ...importing cystine is potentially toxic due to its low solubility, forcing cancer cells with high levels of SLC7A11 (SLC7A11
) to constitutively reduce cystine to the more soluble cysteine. This presents a significant drain on the cellular NADPH pool and renders such cells dependent on the pentose phosphate pathway. Limiting glucose supply to SLC7A11
cancer cells results in marked accumulation of intracellular cystine, redox system collapse and rapid cell death, which can be rescued by treatments that prevent disulfide accumulation. We further show that inhibitors of glucose transporters selectively kill SLC7A11
cancer cells and suppress SLC7A11
tumour growth. Our results identify a coupling between SLC7A11-associated cystine metabolism and the pentose phosphate pathway, and uncover an accompanying metabolic vulnerability for therapeutic targeting in SLC7A11
cancers.
The roles of long non-coding RNAs in cancer metabolism remain largely unexplored. Here we identify FILNC1 (FoxO-induced long non-coding RNA 1) as an energy stress-induced long non-coding RNA by FoxO ...transcription factors. FILNC1 deficiency in renal cancer cells alleviates energy stress-induced apoptosis and markedly promotes renal tumor development. We show that FILNC1 deficiency leads to enhanced glucose uptake and lactate production through upregulation of c-Myc. Upon energy stress, FILNC1 interacts with AUF1, a c-Myc mRNA-binding protein, and sequesters AUF1 from binding c-Myc mRNA, leading to downregulation of c-Myc protein. FILNC1 is specifically expressed in kidney, and is downregulated in renal cell carcinoma; also, its low expression correlates with poor clinical outcomes in renal cell carcinoma. Together, our study not only identifies FILNC1 as a negative regulator of renal cancer with potential clinical value, but also reveals a regulatory mechanism by long non-coding RNAs to control energy metabolism and tumor development.FoxO are commonly down-regulated transcription factors and tumor suppressors in renal cell cancer (RCC). Here, the authors show that upon energy stress FoxOs induce the expression of the long non-coding RNA FILNC1, which inhibits survival of RCC by downregulating c-Myc and c-Myc-dependent metabolic rewiring.
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•Membrane fouling caused by alginate was investigated by fluidized bed ceramic membrane reactor.•Fluidized scouring media reduced fouling significantly regardless of permeate flux ...applied.•Higher pH reduced fouling more due to electrostatic repulsion between alginate and membrane.•Alginate fouling was mitigated by adding divalent cations by enhancing back transport.•Monovalent ions can transform of alginate into rigid, compact and spherocolloidal structures.
Membrane fouling was investigated experimentally by fluidizing non-adsorbed plastic scouring media on flat-tubular ceramic membrane treating a sodium alginate solution as a representative of polysaccharides in wastewater. Fouling rate increased with set-point permeate flux, but it was remarkably reduced by fluidizing the scouring agent regardless of the flux applied. Higher solution pH resulted in more reduction in membrane fouling due to electrostatic repulsion enhanced between alginate foulant and membrane surface which are both negatively charged. The addition of divalent cations such as Ca2+ and Cu2+ mitigated alginate fouling significantly due to the back transport associated with formation of larger particles away from membrane. However, the addition of monovalent cations accelerated the membrane fouling with less effectiveness of the media fluidization in fluidized bed membrane reactor. Adding monovalent ions was thought to transform rigid, compact and spherocolloidal macromolecular structure of alginate into the intramolecular charge shielding to neutralize functional groups.
Brain-Computer Interface (BCI) technology enables users to operate external devices without physical movement. Electroencephalography (EEG) based BCI systems are being actively studied due to their ...high temporal resolution, convenient usage, and portability. However, fewer studies have been conducted to investigate the impact of high spatial resolution of EEG on decoding precise body motions, such as finger movements, which are essential in activities of daily living. Low spatial sensor resolution, as found in common EEG systems, can be improved by omitting the conventional standard of EEG electrode distribution (the international 10–20 system) and ordinary mounting structures (e.g., flexible caps). In this study, we used newly proposed flexible electrode grids attached directly to the scalp, which provided ultra-high-density EEG (uHD EEG). We explored the performance of the novel system by decoding individual finger movements using a total of 256 channels distributed over the contralateral sensorimotor cortex. Dense distribution and small-sized electrodes result in an inter-electrode distance of 8.6 mm (uHD EEG), while that of conventional EEG is 60 to 65 mm on average. Five healthy subjects participated in the experiment, performed single finger extensions according to a visual cue, and received avatar feedback. This study exploits mu (8–12 Hz) and beta (13–25 Hz) band power features for classification and topography plots. 3D ERD/S activation plots for each frequency band were generated using the MNI-152 template head. A linear support vector machine (SVM) was used for pairwise finger classification. The topography plots showed regular and focal post-cue activation, especially in subjects with optimal signal quality. The average classification accuracy over subjects was 64.8 (6.3)%, with the middle versus ring finger resulting in the highest average accuracy of 70.6 (9.4)%. Further studies are required using the uHD EEG system with real-time feedback and motor imagery tasks to enhance classification performance and establish the basis for BCI finger movement control of external devices.
It is now widely accepted that several gene alterations including transcription factors are critically involved in cancer progression and metastasis. Forkhead Box Class O proteins (FoxOs) including ...FoxO1/FKHR, FoxO3/FKHRL1, FoxO4/AFX and FoxO6 transcription factors are known to play key roles in proliferation, apoptosis, metastasis, cell metabolism, aging and cancer biology through their phosphorylation, ubiquitination, acetylation and methylation. Though FoxOs are proved to be mainly regulated by upstream phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3 K)/Akt signaling pathway, the role of FoxOs in cancer progression and metastasis still remains unclear so far. Thus, with previous experimental evidences, the present review discussed the role of FoxOs in association with metastasis related molecules including cannabinoid receptor 1 (CNR1), Cdc25A/Cdk2, Src, serum and glucocorticoid inducible kinases (SGKs), CXCR4, E-cadherin, annexin A8 (ANXA8), Zinc finger E-box-binding homeobox 2 (ZEB2), human epidermal growth factor receptor 2 (HER2) and mRNAs such as miR-182, miR-135b, miR-499-5p, miR-1274a, miR-150, miR-34b/c and miR-622, subsequently analyzed the molecular mechanism of some natural compounds targeting FoxOs and finally suggested future research directions in cancer progression and metastasis.
RNA-binding motif protein 10 (RBM10) is an RNA-binding protein frequently deleted or mutated in lung cancer cells. Recent reports showed that the knockdown of RBM10 in human cancer cells enhances the ...growth of mouse tumor xenografts, suggesting that RBM10 acts as a tumor suppressor. RBM10 also regulates alternative splicing and controls cancer cell proliferation. However, the underlying molecular mechanisms for its tumor suppression role remain largely unclear. Here, we for the first time report that RBM10 can induce apoptosis and inhibit cancer cell proliferation by activating p53. Our analysis of cancer genomic databases showed that patients with wild-type RBM10 and p53 survive longer than do those with mutated p53 or less RBM10. RBM10 overexpression markedly inhibited mitochondrial respiration, cell migration and proliferation of various cancer cells that harbor wild-type p53. Also, RBM10 overexpression elongated p53's half-life by disrupting MDM2-p53 interaction and subsequently repressing p53 ubiquitination, whereas knockdown of RBM10 decreased p53 stability. Altogether, our results demonstrate that RBM10 inhibits cancer cell proliferation and induces apoptosis in part by blocking the MDM2-p53 feedback loop.
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