HIF-1α and HIF-2α Differently Regulate the Radiation Sensitivity of NSCLC Cells

Roig, Eloy Moreno; Groot, Arjan J.; Yaromina, Ala; Hendrickx, Tessa C.; Barbeau, L.; Giuranno, Lorena; Dams, Glenn; Ient, Jonathan; Pimentel, Verónica Olivo; Gisbergen, Marike W. van; Dubois, Ludwig; Vooijs, Marc

doi:10.3390/cells8010045

Cited by 43 publications

(40 citation statements)

References 57 publications

(63 reference statements)

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“…This was confirmed in a recent proof of concept study in 2 different tumor backgrounds (HCT116 and 143B) having a nuclear-encoded NDUFS3 knock-out, where HIF-1α stabilization was abolished, but that tumors were able to re-adapt to the hypoxia response (50). These adaptations to hypoxia are supported by the observed increase in HIF-2 expression in the cybrid mutant xenografts, which also has been evidenced from our recently published work (21).…”

Section: Discussionsupporting

confidence: 82%

“…Cells were lysed and processed as described previously (20,21). Antibodies used were M75 (1:40) (kindly provided by Silvia Pastorekova, Institute of Virology, Slovak Academy of Science, Bratislava, Slovak Republic) against CAIX, anti-HIF-1α (1:250, BD transduction), anti-HIF-2α (1:1.000, NB100-122, Novus biologicals) and anti-β-actin (1:200.000, MP biomedicals).…”

Section: Sds-page and Western Blottingmentioning

confidence: 99%

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Mitochondrial Dysfunction Inhibits Hypoxia-Induced HIF-1α Stabilization and Expression of Its Downstream Targets

et al. 2020

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mtDNA variations often result in bioenergetic dysfunction inducing a metabolic switch toward glycolysis resulting in an unbalanced pH homeostasis. In hypoxic cells, expression of the tumor-associated carbonic anhydrase IX (CAIX) is enhanced to maintain cellular pH homeostasis. We hypothesized that cells with a dysfunctional oxidative phosphorylation machinery display elevated CAIX expression levels. Increased glycolysis was observed for cytoplasmic 143B mutant hybrid (m.3243A>G, >94.5%) cells (p < 0.05) and 143B mitochondrial DNA (mtDNA) depleted cells (p < 0.05). Upon hypoxia (0.2%, 16 h), genetic or pharmacological oxidative phosphorylation (OXPHOS) inhibition resulted in decreased CAIX (p < 0.05), vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1-alpha (HIF-1α) expression levels. Reactive oxygen species (ROS) and prolyl-hydroxylase 2 (PHD2) levels could not explain these observations. In vivo, tumor take (>500 mm 3) took longer for mutant hybrid xenografts, but growth rates were comparable with control tumors upon establishment. Previously, it has been shown that HIF-1α is responsible for tumor establishment. In agreement, we found that HIF-1α expression levels and the pimonidazole-positive hypoxic fraction were reduced for the mutant hybrid xenografts. Our results demonstrate that OXPHOS dysfunction leads to a decreased HIF-1α stabilization and subsequently to a reduced expression of its downstream targets and hypoxic fraction in vivo. In contrast, hypoxia-inducible factor 2-alpha (HIF-2α) expression levels in these xenografts were enhanced. Inhibition of mitochondrial function is therefore an interesting approach to increase therapeutic efficacy in hypoxic tumors.

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Section: Discussionsupporting

confidence: 82%

Section: Sds-page and Western Blottingmentioning

confidence: 99%

Mitochondrial Dysfunction Inhibits Hypoxia-Induced HIF-1α Stabilization and Expression of Its Downstream Targets

et al. 2020

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“…Essential pathways that block E-cadherin and are involved in EMT include the zinc-finger transcriptional factors SNAIL (SNAIL1), SLUG (SNAIL2), TWIST, the ZEB1 [51]. The promoter of the TWIST1 gene contains a HRE which can directly activate TWIST1 expression by binding either HIF-1 or HIF-2 [52,53].…”

Section: Hypoxia and Metastasis: The Implication Of The Hypoxic Effecmentioning

confidence: 99%

Hypoxia: Overview on Hypoxia-Mediated Mechanisms with a Focus on the Role of HIF Genes

Tirpe

Gulei

Ciortea

et al. 2019

IJMS

254

183

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Hypoxia represents a frequent player in a number of malignancies, contributing to the development of the neoplastic disease. This review will discuss the means by which hypoxia powers the mechanisms behind cancer progression, with a majority of examples from lung cancer, the leading malignancy in terms of incidence and mortality rates (the frequent reference toward lung cancer is also for simplification purposes and follow up of the global mechanism in the context of a disease). The effects induced by low oxygen levels are orchestrated by hypoxia-inducible factors (HIFs) which regulate the expression of numerous genes involved in cancer progression. Hypoxia induces epithelial-to-mesenchymal transition (EMT) and metastasis through a complex machinery, by mediating various pathways such as TGF-β, PI3k/Akt, Wnt, and Jagged/Notch. Concomitantly, hypoxic environment has a vast implication in angiogenesis by stimulating vessel growth through the HIF-1α/VEGF axis. Low levels of oxygen can also promote the process through several other secondary factors, including ANGPT2, FGF, and HGF. Metabolic adaptations caused by hypoxia include the Warburg effect—a metabolic switch to glycolysis—and GLUT1 overexpression. The switch is achieved by directly increasing the expression of numerous glycolytic enzymes that are isoforms of those found in non-malignant cells.

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“…Accordingly, 15-LOX-1 was pursued in this study to find out its relationship with radiosensitivity. Recently, 15-LOX-1 was proposed to suppress hypoxia-inducing factor-1 and angiogenesis in several reports [13,14,15,16], which also suggests that 15-LOX-1 is a central factor in radiation sensitivity. However, to date, the relationship between 15-LOX-1 and radiation sensitivity has not been clarified.…”

Section: Introductionmentioning

confidence: 99%

Deficiency of 15-LOX-1 Induces Radioresistance through Downregulation of MacroH2A2 in Colorectal Cancer

Kim

et al. 2019

Cancers

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Despite the importance of radiation therapy, there are few radiation-related markers available for use in clinical practice. A larger catalog of such biomarkers is required to help clinicians decide when radiotherapy should be replaced with a patient-specific treatment. Arachidonate 15-lipoxygenase (15-LOX-1) enzyme is involved in polyunsaturated fatty acid metabolism. When colorectal cancer (CRC) cells were exposed to radiation, 15-LOX-1 was upregulated. To verify whether 15-LOX-1 protects against or induces DNA damage, we irradiated sh15-LOX-1 stable cells. We found that low 15-LOX-1 is correlated with radioresistance in CRC cells. These data suggest that the presence of 15-LOX-1 can be used as a marker for radiation-induced DNA damage. Consistent with this observation, gene-set-enrichment analysis based on microarray experiments showed that UV_RESPONSE was decreased in sh15-LOX-1 cells compared to shCon cells. Moreover, we discovered that the expression of the histone H2A variant macroH2A2 was sevenfold lower in sh15-LOX-1 cells. Overall, our findings present mechanistic evidence that macroH2A2 is transcriptionally regulated by 15-LOX-1 and suppresses the DNA damage response in irradiated cells by delaying H2AX activation.

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HIF-1α and HIF-2α Differently Regulate the Radiation Sensitivity of NSCLC Cells

Cited by 43 publications

References 57 publications

Mitochondrial Dysfunction Inhibits Hypoxia-Induced HIF-1α Stabilization and Expression of Its Downstream Targets

Mitochondrial Dysfunction Inhibits Hypoxia-Induced HIF-1α Stabilization and Expression of Its Downstream Targets

Hypoxia: Overview on Hypoxia-Mediated Mechanisms with a Focus on the Role of HIF Genes

Deficiency of 15-LOX-1 Induces Radioresistance through Downregulation of MacroH2A2 in Colorectal Cancer

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