Research advances in endometriosis-related signaling pathways: A review.

FDX1 enhances endometriosis cell cuproptosis via G6PD-mediated redox homeostasis

The hydrolysis of ATP is the primary source of metabolic energy for eukaryotic cells. Under physiological conditions, cells generally produce more than sufficient levels of ATP to fuel the active biological processes necessary to maintain homeostasis. However, mechanisms underpinning the distribution of ATP to subcellular microenvironments with high local demand remain poorly understood. Intracellular distribution of ATP in normal physiological conditions has been proposed to rely on passive diffusion across concentration gradients generated by ATP producing systems such as the mitochondria and the glycolytic pathway. However, subcellular microenvironments can develop with ATP deficiency due to increases in local ATP consumption. Alternatively, ATP production can be reduced during bioenergetic stress during hypoxia. Mammalian cells therefore need to have the capacity to alter their metabolism and energy distribution strategies to compensate for local ATP deficits while also controlling ATP production. It is highly likely that satisfying the bioenergetic requirements of the cell involves the regulated distribution of ATP producing systems to areas of high ATP demand within the cell. Recently, the distribution (both spatially and temporally) of ATP-producing systems has become an area of intense investigation. Here, we review what is known (and unknown) about intracellular energy production and distribution and explore potential mechanisms through which this targeted distribution can be altered in hypoxia, with the aim of stimulating investigation in this important, yet poorly understood field of research. 

Intracellular energy production and distribution in hypoxia

Endometriosis, characterized by ectopic endometrium growth in the extrauterine environment, is one of the most notable diseases of the female reproductive system. Worldwide, endometriosis affects nearly 10 % of women in their reproductive years and causes a significant decline in quality of life. Despite extensive investigations of endometriosis over the past years, the mechanisms of endometriosis pathogenesis remain unclear. In recent years, metabolic factors have increasingly been considered factors in endometriosis. There is compelling evidence regarding the progress of endometriosis in the context of severe metabolic dysfunction. Hence, the curative strategies and ongoing attempts to conquer endometriosis might start with metabolic pathways. This review focuses on metabolic mechanisms and summarizes current research progress. These findings provide valuable information for the non-intrusive diagnosis of the disease and may contribute to the understanding of the pathogenesis of endometriosis. 

Emerging hallmarks of endometriosis metabolism: A promising target for the treatment of endometriosis.

https://doi.org/10.1016/j.isci.2022.105363

Ovarian tumorB1-mediated heat shock transcription factor 1 deubiquitination is critical for glycolysis and development of endometriosis

Endometriosis (EM) is one of the vanquished wonted causes of chronic pelvic sting in women and is closely associated with infertility. The long-term, complex, systemic, and post-treatment recurrence of EM wreaks havoc on women's quality of life. Extensive metabolic reprogramming (aerobic glycolysis, glucose overweening intake, and high lactate production) and cancer-like changes have been found in EM, which bears striking similarities to tumorigenesis. The key glycolysis regulator PFKFB4 is overexpressed in EM. However, the mechanism of PFKFB4 in EM remains unknown. We found that PFKFB4 was upregulated and was closely related to the progression of EM. We identified focus PIM2 as a new pioneering adjoin protein of PFKFB4. Vigorous biochemical methods were used to confirm that PIM2 phosphorylated site Thr140 of PFKFB4. PIM2 also could enhance PFKFB4 protein expression through the ubiquitin-proteasome pathway. Moreover, PIM2 expression was really corresponding prevalent with PFKFB4 in endometriosis in vivo. Importantly, phosphorylation of PFKFB4 on Thr140 by PIM2 promoted EM glycolysis and cell growth. Our study demonstrates that PIM2 mediates PFKFB4 Thr140 phosphorylation thus regulating glycolysis and EM progression. We illustrated a new mechanism that PIM2 simulated a central upstream partnership in the regulation of PFKFB4, and reveal a novel means of PIM2-PFKFB4 setting EM growth. Our research provided new theoretical support for further clarifying the reprogramming of EM glucose metabolism, and provided new clues for exploring non-contraceptive treatments for EM. 

/pdf/phosphorylation-of-pfkfb4-by-pim2-promotes-anaerobic-28ts1ggn.pdf

Phosphorylation of PFKFB4 by PIM2 promotes anaerobic glycolysis and cell proliferation in endometriosis

This study evaluated whether psychological stress increases the incidence of ovarian cancer. A literature search of the electronic databases PubMed and Web of Science from the date of inception to August 2022 was undertaken. Studies with data on psychosocial factors associated with ovarian cancer incidence were included in this study. A random-effect model meta-analysis was undertaken to estimate these data. We used subgroup analysis to adjust for heterogeneity. A total of 4 articles, 10 sets of data, 8 cohort studies, and 2 case-control studies from 682 records were included in this review. Meta-analyses of the included cohort study subgroups suggested that psychological factors increase the risk of ovarian cancer (effect size = 1.37, 95% CI: 1.20-1.53); the subgroup of case-control studies suggested that psychological factors did not increase ovarian cancer risk (effect size = 0.84, 95% CI: 0.70-0.98). These findings indicate that psychological stress is a possible new risk factor for ovarian cancer.Prospero registration number: CRD42022357983IMPACT STATEMENTWhat is already known on this subject? Psychological stress has been shown to increase the risk of many diseases. The relationship between psychological stress and the incidence of ovarian cancer has not been confirmed.What do the results of this study add? The effect of psychological stress on the risk of ovarian cancer was estimated using meta-analysis as an overall ratio.What are the implications of these findings for clinical practice and/or further research? Relaxing psychological stress and appropriate psychotherapy in clinical settings can help reduce the risk of ovarian cancer.

Psychological factors increase the risk of ovarian cancer.

High‐risk neuroblastoma (HR‐NB) is an aggressive childhood cancer that responds poorly to currently available therapies and is associated with only about a 50% 5‐year survival rate. MYCN amplification is a critical driver of these aggressive tumors, but so far there have not been any approved treatments to effectively treat HR‐NB by targeting MYCN or its downstream effectors. Thus, the identification of novel molecular targets and therapeutic strategies to treat children diagnosed with HR‐NB represents an urgent unmet medical need. Here, we conducted a targeted siRNA screening and identified TATA box‐binding protein‐associated factor RNA polymerase I subunit D, TAF1D, as a critical regulator of the cell cycle and proliferation in HR‐NB cells. Analysis of three independent primary NB cohorts determined that high TAF1D expression correlated with MYCN‐amplified, high‐risk disease and poor clinical outcomes. TAF1D knockdown more robustly inhibited cell proliferation in MYCN‐amplified NB cells compared with MYCN‐non‐amplified NB cells, as well as suppressed colony formation and inhibited tumor growth in a xenograft mouse model of MYCN‐amplified NB. RNA‐seq analysis revealed that TAF1D knockdown downregulates the expression of genes associated with the G2/M transition, including the master cell‐cycle regulator, cell‐cycle‐dependent kinase 1 (CDK1), resulting in cell‐cycle arrest at G2/M. Our findings demonstrate that TAF1D is a key oncogenic regulator of MYCN‐amplified HR‐NB and suggest that therapeutic targeting of TAF1D may be a viable strategy to treat HR‐NB patients by blocking cell‐cycle progression and the proliferation of tumor cells.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/cas.15815

TAF1D promotes proliferation by transcriptionally activating G2/M phase‐related genes in MYCN ‐amplified neuroblastoma

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Phosphorylation of PFKFB4 by PIM2 promotes anaerobic glycolysis and cell proliferation in endometriosis

Psychological factors increase the risk of ovarian cancer.

TAF1D promotes proliferation by transcriptionally activating G2/M phase‐related genes in MYCN ‐amplified neuroblastoma