Manganese superoxide dismutase suppresses hypoxic induction of hypoxia-inducible factor-1α and vascular endothelial growth factor

Wang, Min; Kirk, Jeanie S; Venkataraman, Sujatha; Domann, Frederick E.; Schäfer, Freya; Flanagan, Shawn W.; Weydert, Christine J.; Spitz, Douglas R.; Buettner, Garry R.; Oberley, Larry W.

doi:10.1038/sj.onc.1208986

Cited by 126 publications

(94 citation statements)

References 65 publications

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“…Similarly, cells in which mitochondrial transcription factor A (TFAm) is knocked down, rendering them incapable of making mitochondria, cannot produce reactive oxygen species nor can they stabilize HIF1α under hypoxic conditions 30 . Finally, overexpression of manganese superoxide dismutase (MnSOD, also known as SOD2), the mitochondrial sOD, has been shown to inhibit HIF1α levels, downregulate VEGF and inhibit tumour growth 44,45 .…”

Section: Free Radical Regulation Of Hif1 Under Hypoxic Conditionsmentioning

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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Section: Free Radical Regulation Of Hif1 Under Hypoxic Conditionsmentioning

confidence: 99%

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

2008

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“…Recently, it was reported that HIF-1a induced Mn-SOD and the induced Mn-SOD suppressed HIF-1a upregulation in hypoxic conditions. 47 In addition, HO-1 has been identified as an inducer of Mn-SOD. 24 To explore the involvement of HIF-1a in Mn-SOD expression, we examined Mn-SOD levels in OSCC cells that were transfected with HIF-1a expression vector or HIF-1a-siRNA.…”

Section: Discussionmentioning

confidence: 99%

The involvement of hypoxia‐inducible factor‐1α in the susceptibility to γ‐rays and chemotherapeutic drugs of oral squamous cell carcinoma cells

Sasabe

Zhou

et al. 2006

Intl Journal of Cancer

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The transcription factor hypoxia-inducible factor-1a (HIF-1a) is the key regulator that controls the hypoxic response of mammalian cells. The overexpression of HIF-1a has been demonstrated in many human tumors. However, the role of HIF-1a in the therapeutic efficacy of chemotherapy and radiotherapy in cancer cells is poorly understood. In this study, we investigated the influence of HIF-1a expression on the susceptibility of oral squamous cell carcinoma (OSCC) cells to chemotherapeutic drugs (cis-diamminedichloroplatinum and 5-fluorouracil) and c-rays. Treatment with chemotherapeutic drugs and c-rays enhanced the expression and nuclear translocation of HIF-1a, and the susceptibility of OSCC cells to the drugs and c-rays was negatively correlated with the expression level of HIF-1a protein. The overexpression of HIF-1a induced OSCC cells to become more resistant to the anticancer agents, and down-regulation of HIF-1a expression by small interfering RNA enhanced the susceptibility of OSCC cells to them. In the HIF-1a-knockdown OSCC cells, the expression of P-glycoprotein, heme oxygenase-1, manganese-superoxide dismutase and ceruloplasmin were downregulated and the intracellular levels of chemotherapeutic drugs and reactive oxygen species were sustained at higher levels after the treatment with the anticancer agents. These results suggest that enhanced HIF-1a expression is related to the resistance of tumor cells to chemo-and radio-therapy and that HIF-1a is an effective therapeutic target for cancer treatment. ' 2006 Wiley-Liss, Inc.Key words: hypoxia-inducible factor-1a; chemotherapeutic drugs; g-rays; P-glycoprotein; heme oxygenase-1 Solid tumors generally possess hypoxic areas in their central portion because of decreased vascular supply associated with the effects of treatment and the originally increased energy demand of cancer cells, and the hypoxic tissue is one of the serious matters for consideration in the control of malignant tumors. Most tumor cells possess the ability to undergo apoptosis in response to hypoxic conditions. However, tumor cells can adapt to hypoxic conditions by employing a variety of survival tools, which result in the promotion of cancer cell growth and metastasis. [1][2][3] This adaptation of cancer cells to hypoxia is mainly mediated by the transcription factor hypoxia-inducible factor-1 (HIF-1). 4 HIF-1 is a heterodimeric transcription factor consisting of an oxygen-regulated a subunit (HIF1a) and a stable nuclear factor, HIF-1b/aryl hydrocarbon receptor nuclear translocator (ARNT). Under normoxic conditions, HIF-1a is rapidly degraded by the proteosome after being targeted for ubiquitination. HIF-1a translocates to the nucleus under hypoxic conditions and forms an active complex with HIF-1b; the complex binds to the hypoxia-response element (HRE) in the target genes, which results in the transactivation of these genes. 5 Proteins encoded by such genes contribute to the blood supply, energy production, growth/survival, invasion/metastasis and resistance.It has been frequently rep...

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“…Upon O 2 deprivation the degradation rate of the HIF-1 alpha subunit turn-over is reduced and the protein stabilized. Importantly it has been recently shown that HIF-1 stabilization requires mitochondrial ROS and is inhibited in the presence of high levels of GPx or catalase (116,117). HIF-1 has also been proposed to up-regulate the Mn-SOD promoter although the biological significance of this regulation has not been established (118).…”

Section: Hif-1mentioning

confidence: 99%

Mitochondrial dysfunction in human pathologies

Monsalve¹

2007

Front Biosci

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The integrity of mitochondrial function is fundamental to cell life. The cell demands for mitochondria and their complex integration into cell biology, extends far beyond the provision of ATP. It follows that disturbances of mitochondrial function lead to disruption of cell function, expressed as disease or even death. Mitochondria are major producers of free radical species and also possibly of nitric oxide, and are, at the same time, major targets for oxidative damage. In this review we consider recent developments in our knowledge of how the mitochondrial production of reactive oxygen species (ROS) plays a critical role in several major human pathologies. We will also consider recent advances in our understanding of the molecular mechanisms involved in mitochondrial ROS detoxification.

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Manganese superoxide dismutase suppresses hypoxic induction of hypoxia-inducible factor-1α and vascular endothelial growth factor

Cited by 126 publications

References 65 publications

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

The involvement of hypoxia‐inducible factor‐1α in the susceptibility to γ‐rays and chemotherapeutic drugs of oral squamous cell carcinoma cells

Mitochondrial dysfunction in human pathologies

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