Dual Role of Mitochondrial Reactive Oxygen Species in Hypoxia Signaling: Activation of Nuclear Factor-κB via c-SRC– and Oxidant-Dependent Cell Death

Lluis, Josep M.; Buricchi, Francesca; Chiarugi, Paola; Morales, Albert; Fernández‐Checa, José C.

doi:10.1158/0008-5472.can-07-0515

Cited by 202 publications

(165 citation statements)

References 51 publications

(80 reference statements)

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“…First, HIF-1 activates the survival pathway, acting on inhibition of proapoptotic routes such as Bad and Bid and activation of secretion of prosurvival factors such as VEGF, Bcl-2, and myeloid cell leukemia-1 [51,52]. In addition, in hepatoma cells, mitochondrial ROS due to hypoxia lead to activation of the prosurvival pathway driven by nuclear factor-κB, through oxidation/activation of the kinase Src and phosphorylation of the p65 inhibitor of nuclear factor-κB [51,53]. This is a compulsory protection system from an incremental danger, i.e., the decrease in O 2 .…”

Section: Discussionmentioning

confidence: 99%

HIF-1α stabilization by mitochondrial ROS promotes Met-dependent invasive growth and vasculogenic mimicry in melanoma cells

Comito

Calvani

Giannoni

et al. 2011

Free Radical Biology and Medicine

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139

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The "angiogenic switch" during tumor progression is increasingly recognized as a milestone event in tumorigenesis, although the surprising prometastatic effect of antiangiogenic therapies has recently shaken the scientific community. Tumor hypoxia has been singled out as a possible responsible factor in this prometastatic effect, although the molecular pathways are completely unknown. We report herein that human melanoma cells respond to hypoxia through a deregulation of the mitochondrial release of reactive oxygen species (ROS) by the electron transfer chain complex III. These ROS are mandatory to stabilize hypoxia-inducible factor-1α (HIF-1α), the master transcriptional regulator of the hypoxic response. We found that melanoma cells sense hypoxia-enhancing expression/activation of the Met proto-oncogene, which drives a motogenic escape program. Silencing analyses revealed a definite hierarchy of this process, in which mitochondrial ROS drive HIF-1α stabilization, which in turn activates the Met proto-oncogene. This pathway elicits a clear metastatic program of melanoma cells, enhancing spreading on extracellular matrix, motility, and invasion of 3D matrices, as well as growth of metastatic colonies and the ability to form capillary-like structures by vasculogenic mimicry. Both pharmacological and genetic interference with mitochondrial ROS delivery or Met expression block the hypoxiadriven metastatic program. Hence, we propose that hypoxia-driven ROS act as a primary driving force to elicit an invasive program exploited by aggressive melanoma cells to escape from a hypoxic hostile environment.

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Section: Discussionmentioning

confidence: 99%

HIF-1α stabilization by mitochondrial ROS promotes Met-dependent invasive growth and vasculogenic mimicry in melanoma cells

Comito

Calvani

Giannoni

et al. 2011

Free Radical Biology and Medicine

Self Cite

139

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“…4), suggesting that oxidative stress is a necessary cue in ferritin H activation by rotenone. Several recent studies have reported that in some conditions, especially hypoxia, rotenone reduces mitochondrial ROS generation [34][35][36]. To date there is no clear consensus about the effect of rotenone on mitochondrial ROS generation under various conditions; however, such contradictory reports support the need for further investigation into the intricacies of mechanisms of mitochondrial ROS generation and suppression.…”

Section: Discussionmentioning

confidence: 99%

“…Since inhibition of mitochondrial complex I by rotenone has a potential to induce production of ROS and H 2 O 2 [24], we next investigated whether ferritin H protein synthesis was transiently repressed following rotenone treatment. We exposed NIH3T3 cells to 1 uM rotenone for various times over a period of 24 hrs, and subsequently subjected them to 35 Smethionine/cysteine pulse-labeling and ferritin immunoprecipitation. As shown in Fig.…”

Section: Rotenone Induces Ferritin H Expressionmentioning

confidence: 99%

Role and regulation of ferritin H in rotenone-mediated mitochondrial oxidative stress

Mackenzie

Ray

Tsuji

2008

Free Radical Biology and Medicine

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Tight regulation of intracellular iron levels in response to mitochondrial dysfunction is an important mechanism that prevents oxidative stress, thereby limiting cellular damage. Here, we describe a cytoprotective response involving transcriptional activation of the ferritin H gene in response to the mitochondrial complex I inhibitor and neurotoxic compound, rotenone. Rotenone exposure increased ferritin H mRNA and protein synthesis in NIH3T3 fibroblasts and SH-SY5Y neuroblastoma cells. Transient transfection of a ferritin H promoter-luciferase reporter into NIH3T3 cells showed that ferritin H was transcriptionally activated by rotenone through an antioxidant responsive element (ARE). Chromatin immunoprecipitation assays showed that rotenone treatment enhanced binding of Nrf2 and JunD transcription factors to the ARE. In addition, rotenone induced production of reactive oxygen species (ROS), and pretreatment with N-acetylcysteine abrogated ferritin H mRNA induction by rotenone, suggesting that this response is oxidative stress-mediated. Furthermore, reduced ferritin H expression by siRNA sensitized cells to rotenone-induced apoptosis with enhanced ROS production and annexin V positive cells. Taken together, these results suggest that ferritin H transcription is activated by rotenone via an oxidative stress-mediated pathway leading to ARE activation, and may be critically important to protect cells from mitochondrial dysfunction and oxidative stress.

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“…This then amplified, in a feed-back loop, the effect leading to further pseudo-hypoxia and HIF1a stabilization (Dahia et al, 2005;Cervera et al, 2008). Moreover, hypoxia was shown to further inhibit complex II activity and generate mitochondrial ROS (Paddenberg et al, 2003;Lluis et al, 2007). Finally, hypoxia and probably HIF1a also inhibit ATP synthase, thereby contributing to OxPhos reduction (Campanella et al, 2009).…”

mentioning

confidence: 99%

Mitochondrial respiratory chain complexes: apoptosis sensors mutated in cancer?

2011

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Mutations in cancer cells affecting subunits of the respiratory chain (RC) indicate a central role of oxidative phosphorylation for tumourigenesis. Recent studies have suggested that such mutations of RC complexes impact apoptosis induction. We review here the evidence for this hypothesis, which in particular emerged from work on how complex I and II mediate signals for apoptosis. Both protein aggregates are specifically inhibited for apoptosis induction through different means by exploiting with protease activation and pH change, two widespread but independent features of dying cells. Nevertheless, both converge on forming reactive oxygen species for the demise of the cell. Investigations into these mitochondrial processes will remain a rewarding area for unravelling the causes of tumourigenesis and for discovering interference options.

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Dual Role of Mitochondrial Reactive Oxygen Species in Hypoxia Signaling: Activation of Nuclear Factor-κB via c-SRC– and Oxidant-Dependent Cell Death

Cited by 202 publications

References 51 publications

HIF-1α stabilization by mitochondrial ROS promotes Met-dependent invasive growth and vasculogenic mimicry in melanoma cells

HIF-1α stabilization by mitochondrial ROS promotes Met-dependent invasive growth and vasculogenic mimicry in melanoma cells

Role and regulation of ferritin H in rotenone-mediated mitochondrial oxidative stress

Mitochondrial respiratory chain complexes: apoptosis sensors mutated in cancer?

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