Passing the baton: The HIF switch

Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
Trends in Biochemical Sciences (Impact Factor: 11.23). 07/2012; 37(9):364-72. DOI: 10.1016/j.tibs.2012.06.004
Source: PubMed


Hypoxia is an inadequate oxygen supply to tissues and cells, which can restrict their function. The hypoxic response is primarily mediated by the hypoxia-inducible transcription factors, HIF-1 and HIF-2, which have both overlapping and unique target genes. HIF target gene activation is highly context specific and is not a reliable indicator of which HIF-α isoform is active. For example, in some cell lines, the individual HIFs have specific temporal and functional roles: HIF-1 drives the initial response to hypoxia (<24h) and HIF-2 drives the chronic response (>24h). Here, we review the significance of the HIF switch and the relation between HIF-1 and HIF-2 under both physiological and pathophysiological conditions.

21 Reads
  • Source
    • "The HIF family of transcription factors is made up of three oxygen labile subunits, HIF-1α, HIF-2α and HIF-3α, together with a constitutive aryl hydrocarbon receptor nuclear translocator (ARNT or HIF-1β) (Wang et al., 1995). When oxygen is abundant, HIF-1/2α become modified by specific prolyl hydroxylases (PHDs) and ubiquitylated by the von Hippel–Lindau (VHL) E3 ubiquitin ligase promoting HIFα degradation (Koh and Powis, 2005). When oxygen tension is low (hypoxia), the activity of PHD decreases, binding of VHL is lost, degradation of HIF dampens and consequently it accumulates. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Within 2 hours of infection by Theileria annulata sporozoites bovine macrophages display a 2-4-fold increase in transcription of HIF-1α. Twenty hours post-invasion sporozoites develop into multi-nucleated macroschizonts that transform the infected macrophage into an immortalized, permanently proliferating, hyper-invasive and disease causing leukemia-like cell. Once immortalized Theileria-infected leukocytes can be propagated as cell lines and even though cultivated under normoxic conditions, both infected B cells and macrophages display sustained activation of HIF-1α. Attenuated macrophages used as live vaccines against tropical theileriosis also display HIF-1α activation even though they have lost their tumorigenic phenotype. Here, we review data that ascribes HIF-1α activation to the proliferation status of the infected leukocyte and discuss the possibility that Theileria may have lost its ability to render its host macrophage virulent due to continuous parasite replication in a high ROS environment. We propose a model, where uninfected macrophages have low levels of H2O2 output, whereas virulent infected macrophages produce high amounts of H2O2. Further increase in H2O2 output leads to dampening of infected macrophage virulence, a characteristic of disease-resistant macrophages. At the same time exposure to H2O2 sustains HIF-1α that induces the switch from mitochondrial oxidative phosphorylation to Warburg glycolysis, a metabolic shift that underpins uncontrolled infected macrophage proliferation. We propose that as macroschizonts develop into merozoites and infected macrophage proliferation arrests, HIF-1α levels will decrease and glycolysis will switch back from Warburg to oxidative glycolysis. As Theileria infection transforms its host leukocyte into an aggressive leukemic-like cell we propose that manipulating ROS levels, HIF-1α induction and oxidative over Warburg glycolysis could contribute to improved disease control. Finally, as excess amounts of H2O2 drive virulent Theileria-infected macrophages towards attenuation it highlights how infection-induced pathology and redox balance are intimately linked.
    Full-text · Article · Jan 2015 · Cellular Microbiology
  • Source
    • "Its known genetic background (VHL syndrome) allows us to suspect the hypoxic inductivity of CSPG4. The up-regulation of the CSPG4 at 48 h but not 3 h of oxygen reduction indicates a link to chronic hypoxia, thus revealing CSPG4 as a possible target gene of HIF2a; that fits the HIF2a dependency of VHL syndrome [40], [41]. Furthermore, the increased tumor progression seen in a KRAS-driven lung cancer model upon HIF2a depletion (i.e., HIF2a as a tumor suppressor) is in line with the CSPG4’s lack of pro-malignant features [42]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: CSPG4 marks pericytes, undifferentiated precursors and tumor cells. We assessed whether the shed ectodomain of CSPG4 (sCSPG4) might circulate and reflect potential changes in CSPG4 tissue expression (pCSPG4) due to desmoplastic and malignant aberrations occurring in pancreatic tumors. Serum sCSPG4 was measured using ELISA in test (n = 83) and validation (n = 221) cohorts comprising donors (n = 11+26) and patients with chronic pancreatitis (n = 11+20) or neoplasms: benign (serous cystadenoma SCA, n = 13+20), premalignant (intraductal dysplastic IPMNs, n = 9+55), and malignant (IPMN-associated invasive carcinomas, n = 4+14; ductal adenocarcinomas, n = 35+86). Pancreatic pCSPG4 expression was evaluated using qRT-PCR (n = 139), western blot analysis and immunohistochemistry. sCSPG4 was found in circulation, but its level was significantly lower in pancreatic patients than in donors. Selective maintenance was observed in advanced IPMNs and PDACs and showed a nodal association while lacking prognostic relevance. Pancreatic pCSPG4 expression was preserved or elevated, whereby neoplastic cells lacked pCSPG4 or tended to overexpress without shedding. Extreme pancreatic overexpression, membranous exposure and tissuehigh/seralow-discordance highlighted stroma-poor benign cystic neoplasm. SCA is known to display hypoxic markers and coincide with von-Hippel-Lindau and Peutz-Jeghers syndromes, in which pVHL and LBK1 mutations affect hypoxic signaling pathways. In vitro testing confined pCSPG4 overexpression to normal mesenchymal but not epithelial cells, and a third of tested carcinoma cell lines; however, only the latter showed pCSPG4-responsiveness to chronic hypoxia. siRNA-based knockdowns failed to reduce the malignant potential of either normoxic or hypoxic cells. Thus, overexpression of the newly established conditional hypoxic indicator, CSPG4, is apparently non-pathogenic in pancreatic malignancies but might mark distinct epithelial lineage and contribute to cell polarity disorders. Surficial retention on tumor cells renders CSPG4 an attractive therapeutic target. Systemic 'drop and restoration' alterations accompanying IPMN and PDAC progression indicate that the interference of pancreatic diseases with local and remote shedding/release of sCSPG4 into circulation deserves broad diagnostic exploration.
    Full-text · Article · Jun 2014 · PLoS ONE
  • Source
    • "In contrast, hypoxia is accompanied by robust HIF-1alpha induction in both cell lines whereas the induction of HIF-2alpha is marginal. These findings are coherent with previous work reporting that HIF-1alpha drives the initial response to hypoxia whereas HIF-2alpha is needed for the chronic response [34]. Next, we determined the capacity of HIF to increase the expression of VEGF mRNA. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Colorectal cancer (CRC) is a common tumor type with a high mortality rate, in part due to intrinsic drug resistance. Although bevacizumab, a VEGF-directed neutralizing antibody, is particularly active in this pathology, some patients never respond for reasons not well understood. We here wish to clarify the role of autocrine VEGF signaling in the response of CRC cells to angiogenesis inhibition. Our results show that CRC cells with intrinsic bevacizumab-resistance displayed pronounced upregulation of autocrine HIF-VEGF-VEGFR signaling in response to prolonged bevacizumab exposure whereas the same signaling pathway was downregulated in bevacizumab-sensitive xenografts. Importantly, both bevacizumab-sensitive and -resistant CRC xenografts were sensitive to nintedanib, a small molecule angiokinase inhibitor, which was associated with inhibition of mTORC1. In vitro studies revealed that bevacizumab-resistant cells displayed intrinsically higher HIF-VEGF signaling intensity and hypoxia tolerance compared to their bevacizumab-sensitive counterparts. Interestingly, although nintedanib showed comparable activity toward bevacizumab-sensitive cells under normoxia and hypoxia, the drug was three-fold more toxic to the resistant cells under hypoxia, suggesting that nintedanib attenuated the survival signaling that usually protects these cells from hypoxia-mediated cell death. In conclusion, our findings support a role for autocrine VEGF signaling in the survival of CRC cells to hypoxia and thus to angiogenesis inhibition. We further show that nintedanib, a small molecule angiokinase inhibitor, is active toward CRC models with intrinsic bevacizumab resistance supporting clinical trials of nintedanib in patients that do not respond to bevacizumab, alone or in combination with bevacizumab to increase angiogenesis inhibition.
    Full-text · Article · Jan 2014 · Oncotarget
Show more