At the Crossroads of Apoptosis and Autophagy: Multiple Roles of the Co-Chaperone BAG3 in Stress and Therapy Resistance of Cancer DOI Creative Commons
Donat Kögel, Benedikt Linder, Andreas Brunschweiger

et al.

Cells, Journal Year: 2020, Volume and Issue: 9(3), P. 574 - 574

Published: Feb. 28, 2020

BAG3, a multifunctional HSP70 co-chaperone and anti-apoptotic protein that interacts with the ATPase domain of through its C-terminal BAG plays key physiological role in cellular proteostasis. The HSP70/BAG3 complex determines levels large number selective client proteins by regulating their turnover via two major degradation pathways, i.e. proteasomal macroautophagy. On one hand, BAG3 competes BAG1 for binding to HSP70, thereby preventing proteins. By functionally interacting LC3, also delivers polyubiquitinated autophagy pathway. exerts functions, including an involvement stress responses, proteostasis, cell death regulation, development, cytoskeletal dynamics. Conversely, aberrant function/expression has pathophysiological relevance correlated cardiomyopathies, neurodegeneration, cancer. Evidence obtained recent years underscores fact drives several hallmarks cancer, adhesion, metastasis, angiogenesis, enhanced autophagic activity, apoptosis inhibition. This review provides state-of-the-art overview on therapy resistance particular focus BAG3-dependent modulation apoptotic signaling autophagic/lysosomal activity.

Language: Английский

Nrf2 and Ferroptosis: A New Research Direction for Neurodegenerative Diseases DOI Creative Commons
Xiaohua Song,

Dingxin Long

Frontiers in Neuroscience, Journal Year: 2020, Volume and Issue: 14

Published: April 21, 2020

Ferroptosis is a kind of regulated cell death (RCD) caused by the redox state disorder intracellular microenvironment controlled glutathione peroxidase 4 (GPX4), which inhibited iron chelators and lipophilic antioxidants. In addition to classical regulatory mechanisms, new factors for ferroptosis have been discovered in recent years, such as P53 pathway, ATF3/4 Beclin 1 (BECN1) some non-coding RNA. closely related cancer treatment, neurodegenerative diseases, ischemia-reperfusion organ, neurotoxicity, other particular, field diseases treatment has aroused people's interest. The nuclear factor E2 2 (Nrf2/NFE2L2) proved play key role neurodegeneration disease regulation. promotes progression while expression Nrf2 its target genes (Ho-1, Nqo-1, Trx) declined with aging, therefore, there still insufficient evidence networks diseases. this review, we will provide brief overview well an emphasis on mechanism regulating ferroptosis. We also highlight during process investigate theoretical basis further research relationship between treatment.

Language: Английский

Citations

431
NADPH homeostasis in cancer: functions, mechanisms and therapeutic implications DOI Creative Commons
Huai‐Qiang Ju,

Jin‐Fei Lin,

Tian Tian

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2020, Volume and Issue: 5(1)

Published: Oct. 7, 2020

Abstract Nicotinamide adenine dinucleotide phosphate (NADPH) is an essential electron donor in all organisms, and provides the reducing power for anabolic reactions redox balance. NADPH homeostasis regulated by varied signaling pathways several metabolic enzymes that undergo adaptive alteration cancer cells. The reprogramming of renders cells both highly dependent on this network antioxidant capacity more susceptible to oxidative stress. Modulating unique might be effective strategy eliminate these In review, we summarize current existing literatures homeostasis, including its biological functions, regulatory mechanisms corresponding therapeutic interventions human cancers, providing insights into implications targeting metabolism associated mechanism therapy.

Language: Английский

Citations

362
Renal Cell Carcinoma as a Metabolic Disease: An Update on Main Pathways, Potential Biomarkers, and Therapeutic Targets DOI Open Access

Nicola Antonio di Meo,

Francesco Lasorsa,

Monica Rutigliano

et al.

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(22), P. 14360 - 14360

Published: Nov. 18, 2022

Clear cell renal carcinoma (ccRCC) is the most frequent histological kidney cancer subtype. Over last decade, significant progress has been made in identifying genetic and metabolic alterations driving ccRCC development. In particular, an integrated approach using transcriptomics, metabolomics, lipidomics led to a better understanding of as disease. The profiling this could help define predict its behavior terms aggressiveness, prognosis, therapeutic responsiveness, would be innovative strategy for choosing optimal therapy specific patient. This review article describes current state-of-the-art research on pathways potential applications. addition, clinical implication pharmacometabolomic intervention analyzed, which represents new field novel stage-related patient-tailored strategies according susceptibility classes drugs.

Language: Английский

Citations

108
The role of molecular subtypes and immune infiltration characteristics based on disulfidptosis-associated genes in lung adenocarcinoma DOI Creative Commons
Qi Cui,

Jianmin Ma,

Jinjin Sun

et al.

Aging, Journal Year: 2023, Volume and Issue: unknown

Published: June 13, 2023

Lung adenocarcinoma (LUAD) is the most common type of lung cancer which accounts for about 40% all cancers. Early detection, risk stratification and treatment are important improving outcomes LUAD. Recent studies have found that abnormal accumulation cystine other disulfide occurs in cell under glucose starvation, induces stress increases content bond actin cytoskeleton, resulting death, defined as disulfidptosis. Because study disulfidptosis its infancy, role disease progression still unclear. In this study, we detected expression mutation genes LUAD using a public database. Clustering analysis based on gene was performed differential subtype were analyzed. 7 used to construct prognostic model, causes differences investigated by immune-infiltration analysis, immune checkpoint drug sensitivity analysis. qPCR verify key line (A549) normal bronchial epithelial (BEAS-2B). Since G6PD had highest factor cancer, further verified protein cells western blot, confirmed through colony formation experiment interference with able significantly inhibit proliferation ability cells. Our results provide evidence new ideas individualized precision therapy

Language: Английский

Citations

55
NADPH debt drives redox bankruptcy: SLC7A11/xCT-mediated cystine uptake as a double-edged sword in cellular redox regulation DOI Creative Commons
Xiaoguang Liu, Yilei Zhang, Li Zhuang

et al.

Genes & Diseases, Journal Year: 2020, Volume and Issue: 8(6), P. 731 - 745

Published: Nov. 25, 2020

Cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11; also known as xCT) plays a key role in antioxidant defense by mediating cystine uptake, promoting glutathione synthesis, and maintaining cell survival under oxidative stress conditions. Recent studies showed that, to prevent toxic buildup of highly insoluble inside cells, cancer cells with high expression SLC7A11 (SLC7A11high) are forced quickly reduce more soluble cysteine, which requires substantial NADPH supply from the glucose-pentose phosphate pathway (PPP) route, thereby inducing glucose- PPP-dependency SLC7A11high cells. Limiting glucose results significant "debt", redox "bankruptcy", subsequent death. This review summarizes our current understanding NADPH-generating -consuming pathways, discusses opposing protecting stress–induced death such ferroptosis but starvation–induced death, proposes concept that SLC7A11-mediated uptake acts double-edged sword cellular regulation. A detailed biology may identify metabolic vulnerabilities for therapeutic targeting.

Language: Английский

Citations

102
DNA methylation downregulated ZDHHC1 suppresses tumor growth by altering cellular metabolism and inducing oxidative/ER stress-mediated apoptosis and pyroptosis DOI Creative Commons
Le Xin,

Junhao Mu,

Weiyan Peng

et al.

Theranostics, Journal Year: 2020, Volume and Issue: 10(21), P. 9495 - 9511

Published: Jan. 1, 2020

Cancer progression is an intricate biological process profiled by not only unscheduled proliferation, but also altered metabolism mechanisms. In this article, we introduced a novel tumor suppressor gene (TSG), Zinc Finger DHHC-Type Containing 1 (ZDHHC1, known as ZNF377), frequently silenced due to epigenetic modification among various cancers, which exerts significant anti-tumor effects through metabolic regulation. Methods: Quantitative reversed-transcription PCR (qRT-PCR), reverse transcription (RT-PCR) and Western blot were employed demonstrate transcriptional protein levels of targeted regulators. Methylation ZDHHC1 promoter was detected bisulfite genomic sequencing (BGS) methylation specific (MSP). Proteomics analyzed isobaric tags for relative absolute quantitation (iTRAQ) gas chromatography-mass spectrometry (GC-MS) utilized metabolomics analysis. Cellular functions examined via corresponding approaches. Nude mice used xenograft models. Indirect immunofluorescence staining obtain precise location expression target proteins. Oxidative ER stress indicators using kits. Results: We found that in multiple cells specimens methylation. Restoration can curb cancer cell stimulating apoptosis cycle arrest, repressing metastasis, reversing EMT transition stemness. ZDHHC1's salient abilities recognized vivo well. Metabolomic proteomic analyses predicted inhibitory role glucose pathways CYGB-dependent manner, pentose phosphate pathway (PPP), validated examining key factors. Moreover, unraveled dedicates the increment oxidative endoplasmic reticulum (ER) promote pyroptosis anticancer purposes. Conclusion: Our study first time indicates potential tumor-suppressor methylation, capable negatively regulating metabolisms while expedite death induction apoptosis, be exploited development new prevention therapies.

Language: Английский

Citations

80
NF-κB-inducing kinase maintains T cell metabolic fitness in antitumor immunity DOI

Meidi Gu,

Xiaofei Zhou, Jee Hyung Sohn

et al.

Nature Immunology, Journal Year: 2021, Volume and Issue: 22(2), P. 193 - 204

Published: Jan. 4, 2021

Language: Английский

Citations

79
c-MYC-directed NRF2 drives malignant progression of head and neck cancer via glucose-6-phosphate dehydrogenase and transketolase activation DOI Creative Commons

Ya-Chu Tang,

Jenn-Ren Hsiao,

Shih-Sheng Jiang

et al.

Theranostics, Journal Year: 2021, Volume and Issue: 11(11), P. 5232 - 5247

Published: Jan. 1, 2021

Rationale: NRF2, a redox sensitive transcription factor, is up-regulated in head and neck squamous cell carcinoma (HNSCC), however, the associated impact regulatory mechanisms remain unclear. Methods: The protein expression of NRF2 HNSCC specimens was examined by IHC. effect c-MYC on validated ChIP-qPCR, RT-qPCR western blot. impacts malignant progression were determined through genetic manipulation pharmacological inhibition vitro vivo. gene-set enrichment analysis (GSEA) data cDNA microarray combined with RT-qPCR, blot, transwell migration/ invasion, proliferation soft agar colony formation assays used to investigate NRF2. Results: positively correlated features HNSCC. In addition, carcinogens, such as nicotine arecoline, trigger c-MYC-directed activation cells. reprograms wide range cancer metabolic pathways most notable pentose phosphate pathway (PPP). Furthermore, glucose-6-phosphate dehydrogenase (G6PD) transketolase (TKT) are critical downstream effectors that drive HNSCC; coherently expressed signature NRF2/G6PD/TKT gene set potential prognostic biomarker for prediction patient overall survival. Notably, G6PD- TKT-regulated nucleotide biosynthesis more important than regulation determining Conclusions: Carcinogens activation. Over-activation promotes reprogramming TKT-mediated biosynthesis. Targeting NRF2-directed cellular metabolism an effective strategy development novel treatments cancer.

Language: Английский

Citations

76
G6PD inhibits ferroptosis in hepatocellular carcinoma by targeting cytochrome P450 oxidoreductase DOI
Fei Cao,

Anguo Luo,

Chaowen Yang

et al.

Cellular Signalling, Journal Year: 2021, Volume and Issue: 87, P. 110098 - 110098

Published: July 26, 2021

Language: Английский

Citations

76
LINC00242/miR-1-3p/G6PD axis regulates Warburg effect and affects gastric cancer proliferation and apoptosis DOI Creative Commons
Peng Deng, Kai Li, Feng Gu

et al.

Molecular Medicine, Journal Year: 2021, Volume and Issue: 27(1)

Published: Jan. 29, 2021

Reprogrammed glucose metabolism of enhanced Warburg effect (or aerobic glycolysis) is considered as a hallmark cancer. Long non-coding RNAs (lncRNAs) have been certified to play crucial role in tumor progression. The current study aims inquire into the potential regulatory mechanism long intergenic non-protein coding RNA 242 (LINC00242) on glycolysis gastric cancer.LINC00242, miR-1-3p and G6PD expression levels cancer tissues cells were determined by qRT-PCR. Cell apoptosis or viability examined Flow cytometry MTT assay. Western blot was utilized investigate protein levels. Immunohistochemical (IHC) hematoxylin eosin (H&E) staining used for histopathological detection. targeted relationship between LINC00242 verified luciferase reporter gene Nude mouse xenograft detect formation vivo.LINC00242 high-expressed cells, positively correlated with G6PD. Silencing within prominently inhibited cell proliferation vitro relieved tumorigenesis vivo. predicted directly target both Overexpression suppressed glycolysis. competitively combined miR-1-3p, therefore relieving miR-1-3p-mediated suppression G6PD.LINC00242 plays stimulative via regulation miR-1-3p/ axis, affecting proliferation.

Language: Английский

Citations

62