Oxygen-Mediated Suppression of CD8+ T Cell Proliferation by Macrophages: Role of Pharmacological Inhibitors of HIF Degradation.
Ontology highlight
ABSTRACT:
SUBMITTER: Gojkovic M
PROVIDER: S-EPMC8153186 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:A line of studies strongly suggest that the intravenous anesthetic, propofol, suppresses mitochondrial oxygen metabolism. It is also indicated that propofol induces the cell death in a reactive oxygen species (ROS)-dependent manner. Because hypoxia-inducible factor 1 (HIF-1) is a transcription factor which is involved in cellular metabolic reprogramming by modulating gene expressions of enzymes including glycolysis pathway and oxygen utilization of mitochondria, we examined the functional role of HIF-1 activity in propofol-induced cell death. The role of HIF-1 activity on oxygen and energy metabolisms and propofol-induced cell death and caspase activity was examined in renal cell-derived RCC4 cells: RCC4-EV cells which lack von Hippel-Lindau protein (VHL) protein expression and RCC4-VHL cells, which express exogenous VHL, and in neuronal SH-SY5Y cells. It was demonstrated that HIF-1 is involved in suppressing oxygen consumption and facilitating glycolysis in cells and that the resistance to propofol-induced cell death was established in a HIF-1 activation-dependent manner. It was also demonstrated that HIF-1 activation by treatment with HIF?-hydroxylase inhibitors such as n-propyl gallate and dimethyloxaloylglycine, alleviated the toxic effects of propofol. Thus, the resistance to propofol toxicity was conferred by HIF-1 activation by not only genetic deletion of VHL but also exposure to HIF?-hydroxylase inhibitors.
| S-EPMC5997661 | biostudies-literature
Project description:Overexpression of NQO1 is associated with poor prognosis in human cancers including breast, colon, cervix, lung and pancreas. Yet, the molecular mechanisms underlying the pro-tumorigenic capacities of NQO1 have not been fully elucidated. Here we show a previously undescribed function for NQO1 in stabilizing HIF-1α, a master transcription factor of oxygen homeostasis that has been implicated in the survival, proliferation and malignant progression of cancers. We demonstrate that NQO1 directly binds to the oxygen-dependent domain of HIF-1α and inhibits the proteasome-mediated degradation of HIF-1α by preventing PHDs from interacting with HIF-1α. NQO1 knockdown in human colorectal and breast cancer cell lines suppresses HIF-1 signalling and tumour growth. Consistent with this pro-tumorigenic function for NQO1, high NQO1 expression levels correlate with increased HIF-1α expression and poor colorectal cancer patient survival. These results collectively reveal a function of NQO1 in the oxygen-sensing mechanism that regulates HIF-1α stability in cancers.
| S-EPMC5171868 | biostudies-literature
Project description:Tumour hypoxia promotes the accumulation of the otherwise oxygen-labile hypoxia-inducible factor (HIF)-alpha subunit whose expression is associated with cancer progression, poor prognosis and resistance to conventional radiation and chemotherapy. The oxygen-dependent degradation of HIF-alpha is carried out by the von Hippel-Lindau (VHL) protein-containing E3 that directly binds and ubiquitylates HIF-alpha for subsequent proteasomal destruction. Thus, the cellular proteins involved in the VHL-HIF pathway have been recognized as attractive molecular targets for cancer therapy. However, the various compounds designed to inhibit HIF-alpha or HIF-downstream targets, although promising, have shown limited success in the clinic. In the present study, we describe the bioengineering of VHL protein that removes the oxygen constraint in the recognition of HIF-alpha while preserving its E3 enzymatic activity. Using speckle variance-optical coherence tomography (sv-OCT), we demonstrate the dramatic inhibition of angiogenesis and growth regression of human renal cell carcinoma xenografts upon adenovirus-mediated delivery of the bioengineered VHL protein in a dorsal skin-fold window chamber model. These findings introduce the concept and feasibility of 'bio-tailored' enzymes in the treatment of HIF-overexpressing tumours.
| S-EPMC3378113 | biostudies-literature
Project description:The response to hypoxia in animals involves the expression of multiple genes regulated by the αβ-hypoxia-inducible transcription factors (HIFs). The hypoxia-sensing mechanism involves oxygen limited hydroxylation of prolyl residues in the N- and C-terminal oxygen-dependent degradation domains (NODD and CODD) of HIFα isoforms, as catalysed by prolyl hydroxylases (PHD 1-3). Prolyl hydroxylation promotes binding of HIFα to the von Hippel-Lindau protein (VHL)-elongin B/C complex, thus signalling for proteosomal degradation of HIFα. We reveal that certain PHD2 variants linked to familial erythrocytosis and cancer are highly selective for CODD or NODD. Crystalline and solution state studies coupled to kinetic and cellular analyses reveal how wild-type and variant PHDs achieve ODD selectivity via different dynamic interactions involving loop and C-terminal regions. The results inform on how HIF target gene selectivity is achieved and will be of use in developing selective PHD inhibitors.
| S-EPMC5007464 | biostudies-literature
Project description:In this study, we investigated the role of Nur77, an orphan nuclear receptor, in HIF-alpha transcriptional activity. We found that Nur77 associates and stabilizes HIF-1alpha via indirect interaction. Nur77 was found to interact with pVHL in vivo via the alpha-domain of pVHL. By binding to pVHL, Nur77 competed with elongin C for pVHL binding. Moreover, Nur77-binding to pVHL inhibited the pVHL-mediated ubiquitination of HIF-1alpha and ultimately increased the stability and transcriptional activity of HIF-1alpha. The ligand-binding domain of Nur77 was found to interact with pVHL and the expression of this ligand-binding domain was sufficient to stabilize and transactivate HIF-1alpha. Under the conditions that cobalt chloride was treated or pVHL was knocked down, Nur77 could not stabilize HIF-alpha. Moreover, Nur77 could not further stabilize HIF-2alpha in A498/VHL stable cells, which is consistent with our finding that Nur77 indirectly stabilizes HIF-alpha by binding to pVHL. Thus, our results suggest that an orphan nuclear receptor Nur77 binds to pVHL, thereby stabilizes and increases HIF-alpha transcriptional activity under the non-hypoxic conditions.
| S-EPMC2679322 | biostudies-literature
Project description:Many human diseases are characterized by the development of tissue hypoxia. Hypoxia-inducible factor (HIF) is a transcription factor that regulates fundamental cellular processes in response to changes in oxygen concentration, such as angiogenesis, survival, and alterations in metabolism. The levels of HIF-1? subunit are increased in most solid tumors not only by low oxygen but also by growth factors and oncogenes and correlate with patient prognosis and treatment failure. The link between HIF-1? and apoptosis, a major determinant of cancer progression and treatment outcome, is poorly understood. Here we show that HIF-1? protects against drug-induced apoptosis by antagonizing the function of the tumor suppressor p53. HIF-1? upregulation induced proteasomal degradation of homeodomain-interacting protein kinase-2 (HIPK2), the p53 apoptotic activator. Inhibition of HIF-1? by siRNA, HIF-1?-dominant negative or by zinc re-established the HIPK2 levels and the p53-mediated chemosensitivity in tumor cells. Our findings identify a novel circuitry between HIF-1? and p53, and provide a paradigm for HIPK2 dictating cell response to antitumor therapies.
| S-EPMC3047137 | biostudies-literature
Project description:Transient receptor potential melastatin subfamily member 7 (TRPM7) was essential in the growth and metastatic ability of prostate cancer cells. However, the effects and the relevant molecular mechanisms of TRPM7 on metastasis of prostate cancer under hypoxic atmosphere remain unclear. This study investigated the role of TRPM7 in the metastatic ability of androgen-independent prostate cancer cells under hypoxia. First, data mining was carried out to disclose the relationship between the TRPM7 gene level and the survival of prostate cancer patients. Specific siRNAs were used to knockdown target genes. Western blotting and qPCR were employed to determine protein and gene expression, respectively. The gene transcription activity was evaluated by luciferase activity assay of promoter gene. The protein interaction was determined by coimmunoprecipitation. Wound healing and transwell assays were employed to evaluated cell migration and invasion, respectively. Open access database results showed that high expression of TRPM7 was closely related to the poor survival of prostate cancer patients. Hypoxia simultaneously increased TRPM7 expression and induced HIF-1? accumulation in androgen-independent prostate cancer cells. Knockdown of TRPM7 significantly promoted HIF-1? degradation through the proteasome and inhibited EMT changes in androgen-independent prostate cancer cells under hypoxic condition. Moreover, TRPM7 knockdown increased the phosphorylation of RACK1 and strengthened the interaction between RACK1 and HIF-1? but attenuated the binding of HSP90 to HIF-1?. Whereas knockdown of RACK1 increased the binding of HSP90 to HIF-1?. Furthermore, both TRPM7 and HIF-1? knockdown significantly suppressed hypoxia-induced Annexin A1 protein expression, and suppression of HIF-1?/Annexin A1 signaling significantly inhibited hypoxia-induced cell migration and invasion of androgen-independent prostate cancer cells. Our findings demonstrate that TRPM7 knockdown promotes HIF-1? degradation via an oxygen-independent mechanism involving increased binding of RAKC1 to HIF-1?, and TRPM7-HIF-1?-Annexin A1 signaling axis plays a crucial role in the EMT, cell migration, and invasion of androgen-independent prostate cancer cells under hypoxic conditions.
| S-EPMC7079255 | biostudies-literature
Project description:Apoptosis-induced proliferation (AiP) is a compensatory mechanism to maintain tissue size and morphology following unexpected cell loss during normal development, and may also be a contributing factor to cancer and drug resistance. In apoptotic cells, caspase-initiated signaling cascades lead to the downstream production of mitogenic factors and the proliferation of neighboring surviving cells. In epithelial cells of Drosophila imaginal discs, the Caspase-9 ortholog Dronc drives AiP via activation of Jun N-terminal kinase (JNK); however, the specific mechanisms of JNK activation remain unknown. Here we show that caspase-induced activation of JNK during AiP depends on an inflammatory response. This is mediated by extracellular reactive oxygen species (ROSs) generated by the NADPH oxidase Duox in epithelial disc cells. Extracellular ROSs activate Drosophila macrophages (hemocytes), which in turn trigger JNK activity in epithelial cells by signaling through the tumor necrosis factor (TNF) ortholog Eiger. We propose that in an immortalized ("undead") model of AiP, signaling back and forth between epithelial disc cells and hemocytes by extracellular ROSs and TNF/Eiger drives overgrowth of the disc epithelium. These data illustrate a bidirectional cell-cell communication pathway with implication for tissue repair, regeneration, and cancer.
| S-EPMC4765900 | biostudies-literature
Project description:HiF-1? is the central protein driving the cellular response to hypoxia. Its accumulation in cancer cells is linked to the appearance of chemoresistant and aggressive tumor phenotypes. As a consequence, understanding the regulation of HiF-1? dynamics is a major issue to design new anti-cancer therapies. In this paper, we propose a model of the hypoxia pathway, involving HiF-1? and its inhibitor pVHL. Based on data from the literature, we made the hypothesis that the regulation of HiF-1? involves two compartments (nucleus and cytoplasm) and a constitutive shuttle of the pVHL protein between them. We first show that this model captures correctly the main features of HiF-1? dynamics, including the bi-exponential degradation profile in normoxia, the kinetics of induction in hypoxia, and the switch-like accumulation. Second, we simulated the effects of a hypoxia/reoxygenation event, and show that it generates a strong instability of HiF-1?. The protein concentration rapidly increases 3 hours after the reoxygenation, and exhibits an oscillating pattern. This effect vanishes if we do not consider compartmentalization of HiF-1?. This result can explain various counter-intuitive observations about the specific molecular and cellular response to the reoxygenation process. Third, we simulated the HiF-1? dynamics in the tumor case. We considered different types of mutations associated with tumorigenesis, and we compared their consequences on HiF-1? dynamics. Then, we tested different therapeutics strategies. We show that a therapeutic decrease of HiF-1? nuclear level is not always correlated with an attenuation of reoxygenation-induced instabilities. Thus, it appears that the design of anti-HiF-1? therapies have to take into account these two aspects to maximize their efficiency.
| S-EPMC4206521 | biostudies-literature
Project description:Hypoxia-inducible factor (HIF)-? isoforms regulate key macrophage (M?) functions during ischemic inflammation. HIF-2? drives proinflammatory cytokine production; however, the requirements for HIF-2? during other key M? functions, including phagocytosis, are unknown. In contrast to HIF-1?, HIF-2? was not required for hypoxic phagocytic uptake. Surprisingly, basal HIF-2? levels under nonhypoxic conditions were necessary and sufficient to suppress phagocytosis. Screening approaches revealed selective induction of the scavenger receptor MARCO, which was required for enhanced engulfment. Chromatin immunoprecipitation identified the antioxidant NRF2 as being directly responsible for inducing Marco Concordantly, Hif-2?-/- M?s exhibited reduced antioxidant gene expression, and inhibition of mitochondrial reactive oxygen species suppressed Marco expression and phagocytic uptake. Ex vivo findings were recapitulated in vivo; the enhanced engulfment phenotype resulted in increased bacterial clearance and cytokine suppression. Importantly, natural induction of Hif-2? by IL-4 also suppressed MARCO-dependent phagocytosis. Thus, unlike most characterized prophagocytic regulators, HIF-2? can act as a phagocytic repressor. Interestingly, this occurs in resting M?s through tempering of steady-state mitochondrial reactive oxygen species. In turn, HIF-2? promotes M? quiescence by blocking a MARCO bacterial-response pathway. IL-4 also drives HIF-2? suppression of MARCO, leading to compromised bacterial immunosurveillance in vivo.
| S-EPMC5101127 | biostudies-literature