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- Xia, HG, et al.
(författare)
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Degradation of HK2 by chaperone-mediated autophagy promotes metabolic catastrophe and cell death
- 2015
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Ingår i: The Journal of cell biology. - : Rockefeller University Press. - 1540-8140 .- 0021-9525. ; 210:5, s. 705-716
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Tidskriftsartikel (refereegranskat)abstract
- Hexokinase II (HK2), a key enzyme involved in glucose metabolism, is regulated by growth factor signaling and is required for initiation and maintenance of tumors. Here we show that metabolic stress triggered by perturbation of receptor tyrosine kinase FLT3 in non–acute myeloid leukemia cells sensitizes cancer cells to autophagy inhibition and leads to excessive activation of chaperone-mediated autophagy (CMA). Our data demonstrate that FLT3 is an important sensor of cellular nutritional state and elucidate the role and molecular mechanism of CMA in metabolic regulation and mediating cancer cell death. Importantly, our proteome analysis revealed that HK2 is a CMA substrate and that its degradation by CMA is regulated by glucose availability. We reveal a new mechanism by which excessive activation of CMA may be exploited pharmacologically to eliminate cancer cells by inhibiting both FLT3 and autophagy. Our study delineates a novel pharmacological strategy to promote the degradation of HK2 in cancer cells.
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- Centeno, D, et al.
(författare)
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Modeling of Intracellular Taurine Levels Associated with Ovarian Cancer Reveals Activation of p53, ERK, mTOR and DNA-damage-sensing-dependent Cell Protection
- 2024
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Ingår i: bioRxiv : the preprint server for biology. - : Cold Spring Harbor Laboratory.
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Loss of treatment-induced ovarian carcinoma (OC) growth suppression poses a major clinical challenge because it leads to disease recurrence. Therefore, new and well-tolerated approaches to maintain OC suppression after standard-of-care treatment are needed. We have profiled ascites as OC tumor microenvironments (TMs) to search for potential components that would exert growth suppression on OC cell cultures. Our investigations revealed that low levels of taurine, a non-proteogenic sulfonic amino acid, were present within OC ascites. Taurine supplementation, beyond levels found in ascites, induced growth suppression without causing cytotoxicity in multiple OC cell cultures, including patient-derived chemotherapy-resistant spheroid and organoid cultures. Suppression of proliferation by taurine was associated with the inhibition of glycolysis, mitochondrial function, and the activation of p21 and TIGAR, theTP53-dependent and independent tumor suppression regulatory pathways. Expression of p21 or TIGAR in various OC cells, in part, mimicked taurine-induced inhibition of OC cell proliferation. Our data support the potential therapeutic value of taurine supplementation in OC after chemotherapy.
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- Shi, Y, et al.
(författare)
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Mutant p53 as a Regulator and Target of Autophagy
- 2021
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Ingår i: Frontiers in oncology. - : Frontiers Media SA. - 2234-943X. ; 10, s. 607149-
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Tidskriftsartikel (refereegranskat)abstract
- One of the most notoriously altered genes in human cancer is the tumor-suppressor TP53, which is mutated with high frequency in more cancers than any other tumor suppressor gene. Beyond the loss of wild-type p53 functions, mutations in the TP53 gene often lead to the expression of full-length proteins with new malignant properties. Among the defined oncogenic functions of mutant p53 is its effect on cell metabolism and autophagy. Due to the importance of autophagy as a stress adaptive response, it is frequently dysfunctional in human cancers. However, the role of p53 is enigmatic in autophagy regulation. While the complex action of the wild-type p53 on autophagy has extensively been described in literature, in this review, we focus on the conceivable role of distinct mutant p53 proteins in regulating different autophagic pathways and further discuss the available evidence suggesting a possible autophagy stimulatory role of mutant p53. Moreover, we describe the involvement of different autophagic pathways in targeting and degrading mutant p53 proteins, exploring the potential strategies of targeting mutant p53 in cancer by autophagy.
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- Vakifahmetoglu-Norberg, H, et al.
(författare)
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The role of mitochondria in metabolism and cell death
- 2017
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Ingår i: Biochemical and biophysical research communications. - : Elsevier BV. - 1090-2104 .- 0006-291X. ; 482:3, s. 426-431
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Tidskriftsartikel (refereegranskat)
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| 16. |
- Zhang, B., et al.
(författare)
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Characterization of the role of the Malate dehydrogenases to lung tumor cell survival
- 2017
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Ingår i: Journal of Cancer. - : Ivyspring International Publisher. - 1837-9664. ; 8:11
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Tidskriftsartikel (refereegranskat)abstract
- Cellular compartmentalization of biochemical processes in eukaryotic cells is critical for many functions including shuttling of reducing equivalents across membranes. Although coordination of metabolic flux between different organelles is vital for cell physiology, its impact on tumor cell survival is not well understood. By using an integrative approach, we have dissected the role of the key metabolic enzymes Malate dehydrogenases (MDH1 and MDH2) to the survival of Nonsmall Cell Lung Carcinomas. Here, we report that while both the MDH1 (cytosolic) and the MDH2 (mitochondrial) enzymes display elevated levels in patients compared to normal counterparts, only high expression of MDH1 is associated with poor prognosis. We further show that the MDH1 enzymatic activity is significantly higher in NSCLC cells than that of MDH2. Accordingly, genetic depletion of MDH1 leads to significantly higher toxicity than depletion of MDH2. These findings provide molecular insights into the metabolic characteristics of the malate isoenzymes and mark MDH1 as a potential therapeutic target in these tumors.
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- Melas, P. A., et al.
(författare)
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Allele-specific programming of Npy and epigenetic effects of physical activity in a genetic model of depression
- 2013
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Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 3, s. e255-
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Tidskriftsartikel (refereegranskat)abstract
- Neuropeptide Y (NPY) has been implicated in depression, emotional processing and stress response. Part of this evidence originates from human single-nucleotide polymorphism (SNP) studies. In the present study, we report that a SNP in the rat Npy promoter (C/T; rs105431668) affects in vitro transcription and DNA-protein interactions. Genotyping studies showed that the C-allele of rs105431668 is present in a genetic rat model of depression (Flinders sensitive line; FSL), while the SNP's T-allele is present in its controls (Flinders resistant line; FRL). In vivo experiments revealed binding of a transcription factor (CREB2) and a histone acetyltransferase (Ep300) only at the SNP locus of the FRL. Accordingly, the FRL had increased hippocampal levels of Npy mRNA and H3K18 acetylation; a gene-activating histone modification maintained by Ep300. Next, based on previous studies showing antidepressant-like effects of physical activity in the FSL, we hypothesized that physical activity may affect Npy's epigenetic status. In line with this assumption, physical activity was associated with increased levels of Npy mRNA and H3K18 acetylation. Physical activity was also associated with reduced mRNA levels of a histone deacetylase (Hdac5). Conclusively, the rat rs105431668 appears to be a functional Npy SNP that may underlie depression-like characteristics. In addition, the achieved epigenetic reprogramming of Npy provides molecular support for the putative effectiveness of physical activity as a non-pharmacological antidepressant.
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- Vakifahmetoglu-Norberg, H, et al.
(författare)
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The unpredictable caspase-2: what can it do?
- 2010
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Ingår i: Trends in cell biology. - : Elsevier BV. - 1879-3088 .- 0962-8924. ; 20:3, s. 150-159
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Tidskriftsartikel (refereegranskat)
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