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Molecular pathways: reactive oxygen species homeostasis in cancer cells and implications for cancer therapy.

ABSTRACT: Reactive oxygen species (ROS) are important in regulating normal cellular processes, but deregulated ROS contribute to the development of various human diseases, including cancers. Cancer cells have increased ROS levels compared with normal cells, because of their accelerated metabolism. The high ROS levels in cancer cells, which distinguish them from normal cells, could be protumorigenic, but are also their Achilles' heel. The high ROS content in cancer cells renders them more susceptible to oxidative stress-induced cell death, and can be exploited for selective cancer therapy. In this review, we describe several potential therapeutic strategies that take advantage of ROS imbalance in cancer cells by further increasing oxidative stress, either alone or in combination with drugs that modulate certain signaling pathways.

SUBMITTER: Nogueira V

PROVIDER: S-EPMC3933310 | biostudies-other | 2013 Aug

REPOSITORIES: biostudies-other

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Molecular pathways: reactive oxygen species homeostasis in cancer cells and implications for cancer therapy.

Nogueira Veronique V Hay Nissim N

Clinical cancer research : an official journal of the American Association for Cancer Research 20130529 16

Reactive oxygen species (ROS) are important in regulating normal cellular processes, but deregulated ROS contribute to the development of various human diseases, including cancers. Cancer cells have increased ROS levels compared with normal cells, because of their accelerated metabolism. The high ROS levels in cancer cells, which distinguish them from normal cells, could be protumorigenic, but are also their Achilles' heel. The high ROS content in cancer cells renders them more susceptible to ox ...[more]

PMID: 23719265

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Project description:KRIT1 is a gene responsible for Cerebral Cavernous Malformations (CCM), a major cerebrovascular disease characterized by abnormally enlarged and leaky capillaries that predispose to seizures, focal neurological deficits, and fatal intracerebral hemorrhage. Comprehensive analysis of the KRIT1 gene in CCM patients has suggested that KRIT1 functions need to be severely impaired for pathogenesis. However, the molecular and cellular functions of KRIT1 as well as CCM pathogenesis mechanisms are still research challenges. We found that KRIT1 plays an important role in molecular mechanisms involved in the maintenance of the intracellular Reactive Oxygen Species (ROS) homeostasis to prevent oxidative cellular damage. In particular, we demonstrate that KRIT1 loss/down-regulation is associated with a significant increase in intracellular ROS levels. Conversely, ROS levels in KRIT1(-/-) cells are significantly and dose-dependently reduced after restoration of KRIT1 expression. Moreover, we show that the modulation of intracellular ROS levels by KRIT1 loss/restoration is strictly correlated with the modulation of the expression of the antioxidant protein SOD2 as well as of the transcriptional factor FoxO1, a master regulator of cell responses to oxidative stress and a modulator of SOD2 levels. Furthermore, we show that the KRIT1-dependent maintenance of low ROS levels facilitates the downregulation of cyclin D1 expression required for cell transition from proliferative growth to quiescence. Finally, we demonstrate that the enhanced ROS levels in KRIT1(-/-) cells are associated with an increased cell susceptibility to oxidative DNA damage and a marked induction of the DNA damage sensor and repair gene Gadd45alpha, as well as with a decline of mitochondrial energy metabolism. Taken together, our results point to a new model where KRIT1 limits the accumulation of intracellular oxidants and prevents oxidative stress-mediated cellular dysfunction and DNA damage by enhancing the cell capacity to scavenge intracellular ROS through an antioxidant pathway involving FoxO1 and SOD2, thus providing novel and useful insights into the understanding of KRIT1 molecular and cellular functions.

Project description:Mitochondrial reactive oxygen species (mtROS) homeostasis plays an essential role in preventing oxidative injury in endothelial cells, an initial step in atherogenesis. Resveratrol (RSV) possesses a variety of cardioprotective activities, however, little is known regarding the effects of RSV on mtROS homeostasis in endothelial cells. Sirt3 is a mitochondrial deacetylase, which plays a key role in mitochondrial bioenergetics and is closely associated with oxidative stress. The goal of the study is to investigate whether RSV could attenuate oxidative injury in endothelial cells via mtROS homeostasis regulation through Sirt3 signaling pathway. We found that pretreatment with RSV suppressed tert-butyl hydroperoxide (t-BHP)-induced oxidative damage in human umbilical vein endothelial cells (HUVECs) by increasing cell viability, inhibiting cell apoptosis, repressing collapse of mitochondrial membrane potential and decreasing mtROS generation. Moreover, the enzymatic activities of isocitrate dehydrogenase 2 (IDH2), glutathione peroxidase (GSH-Px) and manganese superoxide dismutase (SOD2) as well as deacetylation of SOD2 were increased by RSV pretreatment, suggesting RSV notably enhanced mtROS scavenging in t-BHP-induced endothelial cells. Meanwhile, RSV remarkably reduced mtROS generation by promoting Sirt3 enrichment within the mitochondria and subsequent upregulation of forkhead box O3A (FoxO3A)-mediated mitochondria-encoded gene expression of ATP6, CO1, Cytb, ND2 and ND5, thereby leading to increased complex I activity and ATP synthesis. Furthermore, RSV activated the expressions of phosphorylated adenosine monophosphate-activated protein kinase (p-AMPK), peroxisome proliferator-activated receptor gamma coactivator-1? (PGC-1?) and Sirt3, as well as estrogen-related receptor-? (ERR?)-dependent Sirt3 mRNA transcription, which were abolished in the presence of AMPK inhibitor and AMPK, PGC-1? or Sirt3 siRNA transfection, indicating the effects of RSV on mtROS homeostasis regulation were dependent on AMPK-PGC-1?-ERR?-Sirt3 signaling pathway. Our findings indicated a novel mechanism that RSV-attenuated oxidative injury in endothelial cells through the regulation of mtROS homeostasis, which, in part, was mediated through the activation of the Sirt3 signaling pathway.

Dataset Information

Molecular pathways: reactive oxygen species homeostasis in cancer cells and implications for cancer therapy.

Publications

Molecular pathways: reactive oxygen species homeostasis in cancer cells and implications for cancer therapy.

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