المؤلفون: Mitsugu Shimobayashi, Amandine Thomas, Sunil Shetty, Irina C Frei, Bettina K Wölnerhanssen, Diana Weissenberger, Anke Vandekeere, Mélanie Planque, Nikolaus Dietz, Danilo Ritz, Anne Christin Meyer-Gerspach, Timm Maier, Nissim Hay, Ralph Peterli, Sarah-Maria Fendt, Nicolas Rohner, Michael N Hall

المصدر: eLife, Vol 12 (2023)

مصطلحات موضوعية: obesity, glucose, lipid metabolism, adipose tissue, diabetes, selective insulin resistance, Medicine, Science, Biology (General), QH301-705.5

الوصف: Chronically high blood glucose (hyperglycemia) leads to diabetes and fatty liver disease. Obesity is a major risk factor for hyperglycemia, but the underlying mechanism is unknown. Here, we show that a high-fat diet (HFD) in mice causes early loss of expression of the glycolytic enzyme Hexokinase 2 (HK2) specifically in adipose tissue. Adipose-specific knockout of Hk2 reduced glucose disposal and lipogenesis and enhanced fatty acid release in adipose tissue. In a non-cell-autonomous manner, Hk2 knockout also promoted glucose production in liver. Furthermore, we observed reduced hexokinase activity in adipose tissue of obese and diabetic patients, and identified a loss-of-function mutation in the hk2 gene of naturally hyperglycemic Mexican cavefish. Mechanistically, HFD in mice led to loss of HK2 by inhibiting translation of Hk2 mRNA. Our findings identify adipose HK2 as a critical mediator of local and systemic glucose homeostasis, and suggest that obesity-induced loss of adipose HK2 is an evolutionarily conserved mechanism for the development of selective insulin resistance and thereby hyperglycemia.

وصف الملف: electronic resource

العلاقة: https://elifesciences.org/articles/85103Test; https://doaj.org/toc/2050-084XTest

الوصول الحر: https://doaj.org/article/c1e2768af6504e0cbd38f53c60cca042Test

المؤلفون: Catherine S. Blaha, Gopalakrishnan Ramakrishnan, Sang-Min Jeon, Veronique Nogueira, Hyunsoo Rho, Soeun Kang, Prashanth Bhaskar, Alexander R. Terry, Alexandre F. Aissa, Maxim V. Frolov, Krushna C. Patra, R. Brooks Robey, Nissim Hay

المصدر: Nature Communications, Vol 13, Iss 1, Pp 1-20 (2022)

مصطلحات موضوعية: Science

الوصف: Hexokinase 2 expression is markedly induced in cancer cells and contributes to cancer cell metabolism. Here, the authors show that hexokinase 2 can contribute to the metastatic spread of cancer cells independently of its glycolytic function via inhibiting the activity of GSK3β, which in turn elevates the protein levels of the EMT transcription factor SNAIL.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2041-1723Test

الوصول الحر: https://doaj.org/article/78bfbaa457e843ebaad6087dacfee23aTest

المؤلفون: Manan M. Mehta, Samuel E. Weinberg, Elizabeth M. Steinert, Krishan Chhiba, Carlos Alberto Martinez, Peng Gao, Harris R. Perlman, Paul Bryce, Nissim Hay, Navdeep S. Chandel

المصدر: Cancer & Metabolism, Vol 6, Iss 1, Pp 1-18 (2018)

مصطلحات موضوعية: Hexokinase 2, T cells, Tregs, Leukemia, Colitis, LCMV, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract Background T cells and cancer cells utilize glycolysis for proliferation. The hexokinase (1–4) family of enzymes catalyze the first step of glycolysis. Hexokinase 2 (HK2) is one of the most highly upregulated metabolic enzymes in both cancer and activated T cells. HK2 is required for the development and/or growth of cancer in several cancer models, but the necessity of HK2 in T cells is not fully understood. The clinical applicability of HK2 inhibition in cancer may be significantly limited by any potential negative effects of HK2 inhibition on T cells. Therefore, we investigated the necessity of HK2 for T cell function. In order to identify additional therapeutic cancer targets, we performed RNA-seq to compare in vivo proliferating T cells to T cell leukemia. Methods HK2 was genetically ablated in mouse T cells using a floxed Hk2 allele crossed to CD4-Cre. CD4+ and CD8+ cells from mice were characterized metabolically and tested in vitro. T cell function in vivo was tested in a mouse model of colitis, Th2-mediated lung inflammation, and viral infection. Treg function was tested by crossing Hk2-floxed mice to FoxP3-Cre mice. Hematopoietic function was tested by deleting HK2 from bone marrow with Vav1-iCre. RNA-seq was used to compare T cells proliferating in response to virus with primary T-ALL leukemia induced with mutant Notch1 expression. Results We unexpectedly report that HK2 is largely dispensable for in vitro T cell activation, proliferation, and differentiation. Loss of HK2 does not impair in vivo viral immunity and causes only a small impairment in the development of pathological inflammation. HK2 is not required for Treg function or hematopoiesis in vivo. One hundred sixty-seven metabolic genes were identified as being differentially expressed between T cells and leukemia. Conclusions HK2 is a highly upregulated enzyme in cancer and in T cells. The requirement for HK2 in various cancer models has been described previously. Our finding that T cells are able to withstand the loss of HK2 indicates that HK2 may be a promising candidate for cancer therapy. Furthermore, we identify several other potential metabolic targets in T-ALL leukemia that could spare T cell function.

وصف الملف: electronic resource

العلاقة: http://link.springer.com/article/10.1186/s40170-018-0184-5Test; https://doaj.org/toc/2049-3002Test

الوصول الحر: https://doaj.org/article/84278dafdee54bb999a4ec239b5afd5aTest

المؤلفون: Milad J Alasady, Alexander R Terry, Adam D Pierce, Michael C Cavalier, Catherine S Blaha, Kaylin A Adipietro, Paul T Wilder, David J Weber, Nissim Hay

المصدر: PLoS ONE, Vol 16, Iss 8, p e0256238 (2021)

مصطلحات موضوعية: Medicine, Science

الوصف: S100B is frequently elevated in malignant melanoma. A regulatory mechanism was uncovered here in which elevated S100B lowers mRNA and secreted protein levels of interleukin-6 (IL6) and inhibits an autocrine loop whereby IL6 activates STAT3 signaling. Our results showed that S100B affects IL6 expression transcriptionally. S100B was shown to form a calcium-dependent protein complex with the p90 ribosomal S6 kinase (RSK), which in turn sequesters RSK into the cytoplasm. Consistently, S100B inhibition was found to restore phosphorylation of a nuclear located RSK substrate, CREB, which is a potent transcription factor for IL6 expression. Thus, elevated S100B reduces IL6-STAT3 signaling via RSK signaling pathway in malignant melanoma. Indeed, the elevated S100B levels in malignant melanoma cell lines correspond to low levels of IL6 and p-STAT3.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1932-6203Test

الوصول الحر: https://doaj.org/article/9e8cdda96b274951af8b33b4ddfe5607Test

المؤلفون: Lolita Petit, Shan Ma, Joris Cipi, Shun-Yun Cheng, Marina Zieger, Nissim Hay, Claudio Punzo

المصدر: Cell Reports, Vol 23, Iss 9, Pp 2629-2642 (2018)

مصطلحات موضوعية: hexokinase-2, aerobic glycolysis, oxidative phosphorylation, rods, cones, rod metabolism, metabolic coupling, retinitis pigmentosa, Biology (General), QH301-705.5

الوصف: Aerobic glycolysis accounts for ∼80%–90% of glucose used by adult photoreceptors (PRs); yet, the importance of aerobic glycolysis for PR function or survival remains unclear. Here, we further established the role of aerobic glycolysis in murine rod and cone PRs. We show that loss of hexokinase-2 (HK2), a key aerobic glycolysis enzyme, does not affect PR survival or structure but is required for normal rod function. Rods with HK2 loss increase their mitochondrial number, suggesting an adaptation to the inhibition of aerobic glycolysis. In contrast, cones adapt without increased mitochondrial number but require HK2 to adapt to metabolic stress conditions such as those encountered in retinitis pigmentosa, where the loss of rods causes a nutrient shortage in cones. The data support a model where aerobic glycolysis in PRs is not a necessity but rather a metabolic choice that maximizes PR function and adaptability to nutrient stress conditions.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2211124718307113Test; https://doaj.org/toc/2211-1247Test

الوصول الحر: https://doaj.org/article/916cd834449f41b29b5ee5f1be4232abTest

المؤلفون: Dannielle DeWaal, Veronique Nogueira, Alexander R. Terry, Krushna C. Patra, Sang-Min Jeon, Grace Guzman, Jennifer Au, Christopher P. Long, Maciek R. Antoniewicz, Nissim Hay

المصدر: Nature Communications, Vol 9, Iss 1, Pp 1-14 (2018)

مصطلحات موضوعية: Science

الوصف: Hexokinase 2 (HK2) is selectively upregulated in hepatocellular carcinoma (HCC). Here the authors show that HK2 ablation decreases glycolysis and triggers oxidative phosphorylation (OXPHO) rendering HCC more susceptible to the OXPHO inhibitor metformin and to the FDA-approved drug sorafenib.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2041-1723Test

الوصول الحر: https://doaj.org/article/b4eb4726703e40cea6442db1aeb36e9fTest

المؤلفون: Sang-Min Jeon, Nissim Hay

المصدر: Experimental and Molecular Medicine, Vol 50, Iss 4, Pp 1-3 (2018)

مصطلحات موضوعية: Medicine, Biochemistry, QD415-436

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2092-6413Test

الوصول الحر: https://doaj.org/article/f986666edeb1440ab63ed1576a51235cTest

المؤلفون: Bethany A. Kerr, Xiaoxia Z. West, Young-Woong Kim, Yongzhong Zhao, Miroslava Tischenko, Rebecca M. Cull, Timothy W. Phares, Xiao-Ding Peng, Jeremiah Bernier-Latmani, Tatiana V. Petrova, Ralf H. Adams, Nissim Hay, Sathyamangla V. Naga Prasad, Tatiana V. Byzova

المصدر: Nature Communications, Vol 7, Iss 1, Pp 1-18 (2016)

مصطلحات موضوعية: Science

الوصف: The Akt pathway integrates multiple signals, but whether it affects vasculature function is debatable. Here the authors show that Akt pathway shutdown in adult mouse endothelium causes destabilization of vasculature leading to cardiac and retinal dysfunction, due to decreased levels of Jagged1 and impaired Notch signaling.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2041-1723Test

الوصول الحر: https://doaj.org/article/aa2930f6d9ad490f80a89a4237983af6Test

المؤلفون: Veronique Nogueira, Krushna C Patra, Nissim Hay

المصدر: eLife, Vol 7 (2018)

مصطلحات موضوعية: reactive oxygen species, Hexokinase 2, cancer therapy, prostate cancer, Akt, PTEN, Medicine, Science, Biology (General), QH301-705.5

الوصف: Akt activation in human cancers exerts chemoresistance, but pan-Akt inhibition elicits adverse consequences. We exploited the consequences of Akt-mediated mitochondrial and glucose metabolism to selectively eradicate and evade chemoresistance of prostate cancer displaying hyperactive Akt. PTEN-deficient prostate cancer cells that display hyperactivated Akt have high intracellular reactive oxygen species (ROS) levels, in part, because of Akt-dependent increase of oxidative phosphorylation. High intracellular ROS levels selectively sensitize cells displaying hyperactive Akt to ROS-induced cell death enabling a therapeutic strategy combining a ROS inducer and rapamycin in PTEN-deficient prostate tumors in mouse models. This strategy elicited tumor regression, and markedly increased survival even after the treatment was stopped. By contrast, exposure to antioxidant increased prostate tumor progression. To increase glucose metabolism, Akt activation phosphorylated HK2 and induced its expression. Indeed, HK2 deficiency in mouse models of Pten-deficient prostate cancer elicited a marked inhibition of tumor development and extended lifespan.

وصف الملف: electronic resource

العلاقة: https://elifesciences.org/articles/32213Test; https://doaj.org/toc/2050-084XTest

الوصول الحر: https://doaj.org/article/6d4103e6d02a47d7be5bbd23795abd41Test

المؤلفون: Siva Karthik Varanasi, Ujjaldeep Jaggi, Nissim Hay, Barry T Rouse

المصدر: PLoS ONE, Vol 13, Iss 1, p e0191533 (2018)

مصطلحات موضوعية: Medicine, Science

الوصف: Activation of CD4 T cells leads to their metabolic reprogramming which includes enhanced glycolysis, catalyzed through hexokinase enzymes. Studies in some systems indicate that the HK2 isoform is the most up regulated isoform in activated T cells and in this report the relevance of this finding is evaluated in an infectious disease model. Genetic ablation of HK2 was achieved in only T cells and the outcome was evaluated by measures of T cell function. Our results show that CD4 T cells from both HK2 depleted and WT animals displayed similar responses to in vitro stimulation and yielded similar levels of Th1, Treg or Th17 subsets when differentiated in vitro. A modest increase in the levels of proliferation was observed in CD4 T cells lacking HK2. Deletion of HK2 led to enhanced levels of HK1 indicative of a compensatory mechanism. Finally, CD4 T cell mediated immuno-inflammatory responses to a virus infection were similar between WT and HK2 KO animals. The observations that the expression of HK2 appears non-essential for CD4 T cell responses against virus infections is of interest since it suggests that targeting HK2 for cancer therapy may not have untoward effects on CD4 T cell mediated immune response against virus infections.

وصف الملف: electronic resource

العلاقة: http://europepmc.org/articles/PMC5774810?pdf=renderTest; https://doaj.org/toc/1932-6203Test

الوصول الحر: https://doaj.org/article/50ffb849f64840cfaf9da62dd48abcc8Test