The redox biology network in cancer pathophysiology and therapeutics

Manda, Gina; Isvoranu, Gheorghița; Comănescu, Maria; Manea, Adrian; Bütüner, Bilge Debeleç; Korkmaz, Kemal

doi:10.1016/j.redox.2015.06.014

Cited by 124 publications

(80 citation statements)

References 122 publications

(128 reference statements)

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“…Overexpression of NAF-1 resulted in enhanced respiration and glycolytic activity, supporting the possible production of excess metabolic ROS ( Fig. 2 A and B) (4,(20)(21)(22)(23). Remarkably, we were unable, however, to detect elevated levels of ROS in NAF-1(+) cells, compared with controls ( Fig.…”

Section: Enhanced Expression Of Naf-1 Is Associated With Enhanced Metsupporting

confidence: 54%

Breast cancer tumorigenicity is dependent on high expression levels of NAF-1 and the lability of its Fe-S clusters

Darash-Yahana

Pozniak

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

127

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Iron-sulfur (Fe-S) proteins are thought to play an important role in cancer cells mediating redox reactions, DNA replication, and telomere maintenance. Nutrient-deprivation autophagy factor-1 (NAF-1) is a 2Fe-2S protein associated with the progression of multiple cancer types. It is unique among Fe-S proteins because of its 3Cys-1His cluster coordination structure that allows it to be relatively stable, as well as to transfer its clusters to apo-acceptor proteins. Here, we report that overexpression of NAF-1 in xenograft breast cancer tumors results in a dramatic augmentation in tumor size and aggressiveness and that NAF-1 overexpression enhances the tolerance of cancer cells to oxidative stress. Remarkably, overexpression of a NAF-1 mutant with a single point mutation that stabilizes the NAF-1 cluster, NAF-1(H114C), in xenograft breast cancer tumors results in a dramatic decrease in tumor size that is accompanied by enhanced mitochondrial iron and reactive oxygen accumulation and reduced cellular tolerance to oxidative stress. Furthermore, treating breast cancer cells with pioglitazone that stabilizes the 3Cys-1His cluster of NAF-1 results in a similar effect on mitochondrial iron and reactive oxygen species accumulation. Taken together, our findings point to a key role for the unique 3Cys-1His cluster of NAF-1 in promoting rapid tumor growth through cellular resistance to oxidative stress. Cluster transfer reactions mediated by the overexpressed NAF-1 protein are therefore critical for inducing oxidative stress tolerance in cancer cells, leading to rapid tumor growth, and drugs that stabilize the NAF-1 cluster could be used as part of a treatment strategy for cancers that display high NAF-1 expression.Fe-S | ROS | NEET | cancer | NAF-1

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Section: Enhanced Expression Of Naf-1 Is Associated With Enhanced Metsupporting

confidence: 54%

Breast cancer tumorigenicity is dependent on high expression levels of NAF-1 and the lability of its Fe-S clusters

Darash-Yahana

Pozniak

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

127

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“…It is well-known that large amounts of ROS, above a tumor-specific threshold, can induce inhibition of tumor cell proliferation and tumor growth [25][26][27]. Previous studies have shown that GA could promote ROS generation in various types of cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Gambogic Acid Inhibits Malignant Melanoma Cell Proliferation Through Mitochondrial p66shc/ROS-p53/Bax-Mediated Apoptosis

Liang¹,

Zhang²

2016

Cell Physiol Biochem

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Background/Aims: Malignant melanoma has high metastatic potential, is highly resistant to chemotherapy, and has a poor survival rate. Gambogic acid (GA), a polyprenylated xanthone extracted from a traditional Chinese medicinal herb, has been proven to exhibit antitumor activity. The present study aimed to investigate the signaling pathways that mediated GA-induced inhibition of human malignant skin melanoma proliferation. Methods: The study was conducted using A375 cells and the corresponding tumor transplanted in nude mice. Results: Incubation of A375 cells with 1-10 μg/ml GA decreased cell viability and increased apoptosis. GA concentration-dependently increased p66^shc expression and intracellular ROS levels. GA also decreased the oxygen consumption rate and the mitochondrial membrane potential (MMP) in A375 cells. Experimental inhibition of p66^shc by siRNA suppressed GA-induced increase of ROS, decrease of oxygen consumption rate, MMP and cell viability, whilst suppressing GA-induced increase of apoptosis. GA concentration-dependently upregulated p53 and Bax expression in A375 cells. GA also increased p53-TA-luciferase activity and p53-binding to Bax promoter, which was inhibited by Sip53. Experimental inhibition of p53 with Sip53 blocked GA-induced decrease of the oxygen consumption rate and cell viability, and blocked the increase of apoptosis. In tumor-bearing nude mice, GA notably inhibited tumor growth, and this action was suppressed by N-acetylcysteine (NAC), a potent antioxidant, and by PFT-α, a p53 inhibitor. In A375 tumors transplanted in nude mice, GA increased both p66^shc and p53 expression. NAC and PFT-α treatment did not significantly affect p66^shc expression in tumors grown in mice treated with GA. In contrast, both NAC and PFT-α treatment inhibited GA-induced p53 expression in mouse tumors. Conclusion: Results provided novel preclinical insights into the chemotherapeutic use of GA by highlighting the importance of p66^shc/ROS-p53/Bax pathways in the antitumor effect of GA in malignant melanoma.

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“…How oxidative stress is involved in these various steps is the object of revision and investigation. Furthermore, ROS may augment tumor invasion and metastasis by increasing the rates of cell migration [55,56].…”

Section: Discussionmentioning

confidence: 99%

Multivariate discriminant analysis of redox and progression indexes in Cuban AIDS patients with Kaposis sarcoma

Valle¹,

Duque-Vizcaino²,

Calás-Hechavarria³

et al. 2017

Oxid Antioxid Med Sci

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Objectives: Infection by human immunodeficiency virus (HIV) generates sustained reactive oxygen species production. An increasing number of studies underline the pathogenic impact of high-grade local and systemic oxidative stress in the activation of Herpesvirus 8 producing Kaposi's sarcoma (KS) co-infection in acquired immunodeficiency syndrome (AIDS) patients. This study aimed to determine the redox status in AIDS-KS Cuban individuals and to explore the relation between redox and progression variables. Methods: Blood samples were drawn from 99 individuals divided into three groups (33 each one; age range 30-50 years): AIDS, AIDS-KS, and presumable healthy subjects. Total peroxide, malondialdehyde, and advanced oxidation protein products as damage indexes and antioxidant responses (glutathione, peroxidation potential, superoxide dismutase, and catalase) were determined from the blood samples. Furthermore, hematological and hemochemical indexes, progression indexes (viral load, CD4 + T lymphocyte absolute count), and tumoral progression indexes were assessed. Different statistical analyses were done. Results: Compared to healthy subjects, both groups of AIDS patients had significant differences in global indices of damage and antioxidant status. The comparison between the groups revealed that AIDS-KS group had a significantly higher damage and lower antioxidant status compared to the healthy control and AIDS groups. Multivariate statistical analysis clearly separated groups according progression indexes and redox profile, obtaining two canonical functions. Conclusions: These results corroborate that substantial oxidative stress occurs in AIDS condition and also during KS-HIV co-infection with different molecular extension and interdependence to progression indexes. Redox indexes diagnosis should be considered in early diagnostics, prevention and treatment of KS-HIV coinfection, which would be worthwhile to conduct a more comprehensive study and manage of infection.

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The redox biology network in cancer pathophysiology and therapeutics

Cited by 124 publications

References 122 publications

Breast cancer tumorigenicity is dependent on high expression levels of NAF-1 and the lability of its Fe-S clusters

Breast cancer tumorigenicity is dependent on high expression levels of NAF-1 and the lability of its Fe-S clusters

Gambogic Acid Inhibits Malignant Melanoma Cell Proliferation Through Mitochondrial p66shc/ROS-p53/Bax-Mediated Apoptosis

Multivariate discriminant analysis of redox and progression indexes in Cuban AIDS patients with Kaposis sarcoma

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