Mitochondrial reactive oxygen species regulate hypoxic signaling

Hamanaka, Robert B.; Chandel, Navdeep S.

doi:10.1016/j.ceb.2009.08.005

Cited by 272 publications

(240 citation statements)

References 56 publications

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“…Indeed, HIF-1 is stabilized by a redox-dependent pathway, involving inactivation of prolyl hydroxylases, iron-dependent enzymes engaged in degradation of HIFs (20,32). The key role of redox stabilization of HIF-1 has also been underscored by recent data describing that the antitumorigenic effects of NAC and VitC depend on HIF-1 redox stabilization (16).…”

Section: Discussionmentioning

confidence: 91%

Cancer Associated Fibroblasts Exploit Reactive Oxygen Species Through a Proinflammatory Signature Leading to Epithelial Mesenchymal Transition and Stemness

Giannoni

Bianchini

Calorini

et al. 2011

Antioxidants & Redox Signaling

186

170

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Cancer-associated fibroblasts (CAFs) are key determinants in the malignant progression of cancer, supporting tumorigenesis and metastasis. CAFs also mediate epithelial mesenchymal transition (EMT) of tumor cells and their achievement of stem cell traits. We demonstrate that CAFs induce EMT and stemness through a proinflammatory signature, which exploits reactive oxygen species to drive a migratory and aggressive phenotype of prostate carcinoma cells. CAFs exert their propelling role for EMT in strict dependence on cycloxygenase-2 (COX-2), nuclear factor-jB, and hypoxia-inducible factor-1. CAF-secreted metalloproteases elicit in carcinoma cells a Rac1b/COX-2-mediated release of reactive oxygen species, which is mandatory for EMT, stemness, and dissemination of metastatic cells. Tumor growth is abolished, and metastasis formation is severely impaired by RNA interfering-mediated targeting of the proinflammatory signature, thereby supporting the therapeutic targeting of the circuitry COX-2/nuclear factor-jB /hypoxia-inducible factor-1 as a valuable antimetastatic tool affecting cancer cell malignancy.

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Section: Discussionmentioning

confidence: 91%

Cancer Associated Fibroblasts Exploit Reactive Oxygen Species Through a Proinflammatory Signature Leading to Epithelial Mesenchymal Transition and Stemness

Giannoni

Bianchini

Calorini

et al. 2011

Antioxidants & Redox Signaling

186

170

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show abstract

“…Evidence exists that hypoxia can induce ROS and that ROS is even required for hypoxic signaling. 44 We believe that the increased frequency of HSCs in Vegfa ␦/␦ mice is a sign of a stressed situation in the hematopoietic system. Despite the lack of hypoxic Vegfa induction, these HSCs survive if unchallenged, but have a severe disadvantage when competing against WT HSCs.…”

Section: Discussionmentioning

confidence: 99%

Hypoxic induction of vascular endothelial growth factor regulates murine hematopoietic stem cell function in the low-oxygenic niche

Rehn

Olsson

Reckzeh

et al. 2011

Blood

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Hypoxia is emerging as an important characteristic of the hematopoietic stem cell (HSC) niche, but the molecular mechanisms contributing to quiescence, self-renewal, and survival remain elusive. Vascular endothelial growth factor A (VEGFA) is a key regulator of angiogenesis and hematopoiesis. Its expression is commonly regulated by hypoxiainducible factors (HIF) that are functionally induced in low-oxygen conditions and that activate transcription by binding to hypoxia-response elements (HRE).Vegfa is indispensable for HSC survival, mediated by a cell-intrinsic, autocrine mechanism. We hypothesized that a hypoxic HSC microenvironment is required for maintenance or up-regulation of Vegfa expression in HSCs and therefore crucial for HSC survival. We have tested this hypothesis in the mouse model Vegfa ␦/␦ , where the HRE in the Vegfa promoter is mutated, preventing HIF binding. Vegfa expression was reduced in highly purified HSCs from Vegfa ␦/␦ mice, showing that HSCs reside in hypoxic areas. Loss of hypoxiaregulated Vegfa expression increases the numbers of phenotypically defined hematopoietic stem and progenitor cells. However, HSC function was clearly impaired when assessed in competitive transplantation assays. Our data provide further evidence that HSCs reside in a hypoxic microenvironment and demonstrate a novel way in which the hypoxic niche affects HSC fate, via the hypoxia-VEGFA axis. (Blood. 2011; 118(6):1534-1543) IntroductionThe process of blood formation originates with the hematopoietic stem cell (HSC) which is responsible for the life-long supply of mature blood cells through the unique ability to combine selfrenewal and differentiation. During the later stages of mammal development, HSCs are present in the fetal liver (FL) from where they seed the bone marrow (BM), which remains the main site of hematopoiesis throughout adult life. The HSC niche is a term used to describe the location and regulatory microenvironment of HSCs. In the BM, cellular HSC niche components include boneforming osteoblasts 1-2 and perivascular cells, [3][4] that through production of various secreted factors as well as through direct cell-cell interactions can affect HSC behavior. As for location it is thought that HSCs are present at a higher frequency at the endosteum close to the bone surface, because ex vivo labeled HSCs tend to localize to the endosteal areas of the BM. [5][6] However, within these areas HSCs are likely to associate with both osteoblastic and sinusoidal endothelial cells. 7 The FL HSC niche is much less defined than that in the BM, but a candidate FL niche component is a CD3 ϩ Ter119 Ϫ population that can provide HSC support. 8 Apart from HSC regulatory cues such as cell-cell contact and production of soluble factors, it is possible that variations in oxygen availability can affect HSCs, and it has been hypothesized that hypoxia is a characteristic of the HSC niche. 9 Oxygen levels are generally lower in BM compared with peripheral blood (PB). 10 Two studies have demonstrated that fractions of BM that w...

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“…Several reports indicate that hypoxia can induce autophagy, and more recently ROS are emerging as important signaling molecules linking the reduced oxygen tension to the induction of autophagy. 103,104 Intuitively it can be assumed that the levels of intracellular ROS would drop under hypoxic conditions, since O 2 is a substrate for ROS production. Conversely, several groups have found an increase in total intracellular ROS upon exposure to hypoxia.…”

Section: Autophagy Ros and Cancer: A Two-faced Storymentioning

confidence: 99%

ROS-mediated mechanisms of autophagy stimulation and their relevance in cancer therapy

Dewaele¹,

Maes²,

Agostinis³

2010

Autophagy

274

199

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Mitochondrial reactive oxygen species regulate hypoxic signaling

Cited by 272 publications

References 56 publications

Cancer Associated Fibroblasts Exploit Reactive Oxygen Species Through a Proinflammatory Signature Leading to Epithelial Mesenchymal Transition and Stemness

Cancer Associated Fibroblasts Exploit Reactive Oxygen Species Through a Proinflammatory Signature Leading to Epithelial Mesenchymal Transition and Stemness

Hypoxic induction of vascular endothelial growth factor regulates murine hematopoietic stem cell function in the low-oxygenic niche

ROS-mediated mechanisms of autophagy stimulation and their relevance in cancer therapy

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