Enhanced response to radiotherapy in tumours deficient in the function of hypoxia-inducible factor-1

Williams, Kaye J.; Telfer, Brian A.; Xenaki, Dia; Sheridan, Mary R.; Desbaillets, Isabelle; Peters, Hans J.W.; Honess, Davina J.; Harris, Adrian L.; Dachs, Gabi U.; Kogel, Albert van der; Stratford, Ian J.

doi:10.1016/j.radonc.2005.01.009

Cited by 118 publications

(70 citation statements)

References 34 publications

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“…The underlying molecular mechanism involves markedly reduced expression of DNA-PKcs, Ku80 and Ku70, three members of the DNA-dependent protein kinases (DNA-PK), in HIF-1 α -deficient MEFs. Our data were supported by a large number of studies that demonstrated reversal of radio-and chemoresistance by targeting HIF-1 α in various tumor types (Zhang et al , 2004 ;Moeller et al , 2005 ;Williams et al , 2005 ;Brown et al , 2006 ;Li et al , 2006a,b ;Song et al , 2006 ;Sasabe et al , 2007 ). For example, Li et al (2006a,b) showed that the knockdown of HIF-1 α in breast carcinoma cells repressed G 0 /G 1 -phase accumulation and relieved S-phase block, thereby increasing sensitivity to chemotherapy and attenuating tumor growth (Li et al , 2006a,b ).…”

Section: Targeting Hif To Improve Cancer Therapysupporting

confidence: 76%

HIF mediated and DNA damage independent histone H2AX phosphorylation in chronic hypoxia

Wrann

Kaufmann²,

Wirthner³

et al. 2013

Biological Chemistry

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Abstract:The histone variant 2AX (H2AX) is phosphorylated at Serine 139 by the PI3K-like kinase family members ATM, ATR and DNA-PK. Genotoxic stress, such as tumor radioand chemotherapy, is considered to be the main inducer of phosphorylated H2AX ( γ H2AX), which forms distinct foci at sites of DNA damage where DNA repair factors accumulate. γ H2AX accumulation under severe hypoxic/anoxic (0.02 % oxygen) conditions has recently been reported to follow replication fork stalling in the absence of detectable DNA damage. In this study, we found HIF-dependent accumulation of γ H2AX in several cancer cell lines and mouse embryonic fibroblasts exposed to physiologically relevant chronic hypoxia (0.2 % oxygen), which did not induce detectable levels of DNA strand breaks. The hypoxic accumulation of γ H2AX was delayed by the RNAi-mediated knockdown of HIF-1 α or HIF-2 α and further decreased when both HIF-α s were absent. Conversely, basal phosphorylation of H2AX was increased in cells with constitutively stabilized HIF-2 α . These results suggest that both HIF-1 and HIF-2 are involved in γ H2AX accumulation by tumor hypoxia, which might increase a cancer cell ' s capacity to repair DNA damage, contributing to tumor therapy resistance.

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Section: Targeting Hif To Improve Cancer Therapysupporting

confidence: 76%

HIF mediated and DNA damage independent histone H2AX phosphorylation in chronic hypoxia

Wrann

Kaufmann²,

Wirthner³

et al. 2013

Biological Chemistry

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“…Antisense knockdown or pharmacological inhibition of HIF1 synthesis after radiation treatment was shown to also induce significant growth delay in several tumour lines by our group [136][137][138] . In a separate study, Williams et al showed prolonged tumour growth after radiotherapy in a tumour line that is null for HIF1β (also known as ARNT), and therefore unable to render a HIF1 response 139 . The second mechanism of HIF1α stabilization after reoxygenation was related to stress granules 140 .…”

Section: Effects Of Radiation Therapy On Hif1 Activitymentioning

confidence: 99%

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

2008

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Hypoxia and free radicals, such as reactive oxygen and nitrogen species, can alter the function and/or activity of the transcription factor hypoxia-inducible factor 1 (HIF1). Interplay between free radicals, hypoxia and HIF1 activity is complex and can influence the earliest stages of tumour development. The hypoxic environment of tumours is heterogeneous, both spatially and temporally, and can change in response to cytotoxic therapy. Free radicals created by hypoxia, hypoxia-reoxygenation cycling and immune cell infiltration after cytotoxic therapy strongly influence HIF1 activity. HIF1 can then promote endothelial and tumour cell survival. As discussed here, a constant theme emerges: inhibition of HIF1 activity will have therapeutic benefit.Virchow first described the abnormal structure of tumour vessels using contrast agents in human tumours as early as the mid 1800s 1 . A few decades later, Goldman was among the first to suggest that angiogenesis was associated with tumour growth 2 . A number of other investigators in the nineteenth and early twentieth centuries evaluated tumour angiogenesis, using techniques such as microangiography, vascular casting and window chamber models. Warren has reviewed this early work in great detail 3 . Folkman illuminated the crucial role of tumour angiogenesis by hypothesizing that tumour growth was dependent upon angiogenesis and that, if angiogenesis could be inhibited, it could maintain tumour deposits in a quiescent state 4 . These early works set the stage for the concept that tumours require angiogenesis to provide a nutrient supply. Although it is well-established that angiogenesis occurs in nearly all human solid tumours, it does not occur in an efficient manner, leading to spatial and temporal inadequacies in delivery of oxygen and other nutrients. These inefficiencies in nutrient delivery lead to a brutal cycle of unsatisfied demand by the tumour, which drives continued aberrant angiogenesis.The transcription factor hypoxia-inducible factor 1 (HIF1) plays an important part in tumour progression by upregulating genes that control angiogenesis, meta-stasis and resistance to oxidative stress. It also controls the switch to anaerobic metabolism, which can maintain cell NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript viability under hypoxic conditions. Further, HIF1 activity can promote treatment resistance by promoting endothelial and tumour cell survival after cytotoxic therapy. The mechanisms that control HIF1 activity are complex and are influenced by microenvironmental factors involving hypoxia, oxidative and nitrosative stress.In this Review we will discuss four important and interrelated aspects of tumour hypoxia. First, we will define the hypoxic response, discussing its relevance in influencing tumour cell survival, behaviour and angiogenesis. We will examine the physiological factors that contribute to hypoxia, emphasizing a perspective based on spatial and temporal dysfunction of tumour microcirculation. The question of whethe...

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“…This can be of special interest for tumor therapy of hypoxic tumors because HIF1␣ can increase the tumor's resistance to chemotherapeutic agents and radiotherapy (71).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Glycolytic Enzymes Mediated by Pharmacologically Activated p53

Zawacka-Pankau

Grinkevich

Hünten

et al. 2011

Journal of Biological Chemistry

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Background: High dependence of cancer cells on glycolysis is a good target for cancer therapy. Results: Tumor suppressor p53 represses the expression of key regulators of metabolic genes HIF1a and c-Myc and glucose transporters GLUT1 and GLUT12. Conclusion: Blocking ATP production network by pharmacologically activated p53 contributes to cancer cell death. Significance: Tumor-selective killing by reconstituted p53 might be in part due to inhibition of glycolysis.

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Enhanced response to radiotherapy in tumours deficient in the function of hypoxia-inducible factor-1

Cited by 118 publications

References 34 publications

HIF mediated and DNA damage independent histone H2AX phosphorylation in chronic hypoxia

HIF mediated and DNA damage independent histone H2AX phosphorylation in chronic hypoxia

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

Inhibition of Glycolytic Enzymes Mediated by Pharmacologically Activated p53

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