Cytoglobin, a Novel Member of the Globin Family, Protects Kidney Fibroblasts against Oxidative Stress under Ischemic Conditions

Nishi, Hiroshi; Inagi, Reiko; Kawada, Norifumi; Yoshizato, Katsutoshi; Mimura, Imari; Fujita, Toshiro; Nangaku, Masaomi

doi:10.1016/j.ajpath.2010.11.011

Cited by 52 publications

(49 citation statements)

References 49 publications

(56 reference statements)

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“…Human neuroblastoma cells with overexpressed CYGB showed significant protection from oxidative damage induced by H 2 O 2 [6] or a singlet oxygen generator [7]. Treatment with CYGB siRNA enhanced the cellular ROS levels in fibroblasts from CYGB transgenic rat kidney [8]. In melanocytes, highly enriched CYGB may act as a ROS scavenger, similar to melanin.…”

Section: Discussionmentioning

confidence: 96%

Melanoma Transition Is Frequently Accompanied by a Loss of Cytoglobin Expression in Melanocytes: A Novel Expression Site of Cytoglobin

et al. 2014

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The tissue distribution and function of hemoglobin or myoglobin are well known; however, a newly found cytoglobin (CYGB), which also belongs to the globin family, remains to be characterized. To assess its expression in human malignancies, we sought to screen a number of cell lines originated from many tissues using northern blotting and real time PCR techniques. Unexpectedly, we found that several, but not all, melanoma cell lines expressed CYGB mRNA and protein at much higher levels than cells of other origins. Melanocytes, the primary origin of melanoma, also expressed CYGB at a high level. To verify these observations, immunostaining and immunoblotting using anti-CYGB antibody were also performed. Bisulfite-modified genomic sequencing revealed that several melanoma cell lines that abrogated CYGB expression were found to be epigenetically regulated by hypermethylation in the promoter region of CYGB gene. The RNA interference-mediated knockdown of the CYGB transcript in CYGB expression-positive melanoma cell lines resulted in increased proliferation in vitro and in vivo. Flow cytometric analysis using 2′-, 7′-dichlorofluorescein diacetate (DCFH-DA), an indicator of reactive oxygen species (ROS), revealed that the cellular ROS level may be involved in the proliferative effect of CYGB. Thus, CYGB appears to play a tumor suppressive role as a ROS regulator, and its epigenetic silencing, as observed in CYGB expression-negative melanoma cell lines, might function as an alternative pathway in the melanocyte-to-melanoma transition.

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Section: Discussionmentioning

confidence: 96%

Melanoma Transition Is Frequently Accompanied by a Loss of Cytoglobin Expression in Melanocytes: A Novel Expression Site of Cytoglobin

et al. 2014

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“…83 Additionally, during ischemia, CYGB protects kidney fibroblasts from the damaging actions of oxidative stress. 84 More recently, a dichotomous role for CYGB has been demonstrated in lung adenocarcinoma cells. 85 According to this study, during normoxia and in the absence of oxidative stress, CYGB conferred tumor suppressor action.…”

Section: Discussionmentioning

confidence: 99%

Aryl Hydrocarbon Receptor Ligand 5F 203 Induces Oxidative Stress That Triggers DNA Damage in Human Breast Cancer Cells

McLean¹,

Watkins²,

Campbell³

et al. 2015

Chem. Res. Toxicol.

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Breast tumors often show profound sensitivity to exogenous oxidative stress. Investigational agent 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203) induces aryl hydrocarbon receptor (AhR)-mediated DNA damage in certain breast cancer cells. Since AhR agonists often elevate intracellular oxidative stress, we hypothesize that 5F 203 increases reactive oxygen species (ROS) to induce DNA damage, which thwarts breast cancer cell growth. We found that 5F 203 induced single-strand break formation. 5F 203 enhanced oxidative DNA damage that was specific to breast cancer cells sensitive to its cytotoxic actions, as it did not increase oxidative DNA damage or ROS formation in nontumorigenic MCF-10A breast epithelial cells. In contrast, AhR agonist and procarcinogen benzo[a]pyrene and its metabolite, 1,6-benzo[a]pyrene quinone, induced oxidative DNA damage and ROS formation, respectively, in MCF-10A cells. In sensitive breast cancer cells, 5F 203 activated ROS-responsive kinases: c-Jun-N-terminal kinase (JNK) and p38 mitogen activated protein kinase (p38). AhR antagonists (alpha-naphthoflavone, CH223191) or antioxidants (N-acetyl-l-cysteine, EUK-134) attenuated 5F 203-mediated JNK and p38 activation, depending on the cell type. Pharmacological inhibition of AhR, JNK, or p38 attenuated 5F 203-mediated increases in intracellular ROS, apoptosis, and single-strand break formation. 5F 203 induced the expression of cytoglobin, an oxidative stress-responsive gene and a putative tumor suppressor, which was diminished with AhR, JNK, or p38 inhibition. Additionally, 5F 203-mediated increases in ROS production and cytoglobin were suppressed in AHR100 cells (AhR ligand-unresponsive MCF-7 breast cancer cells). Our data demonstrate 5F 203 induces ROS-mediated DNA damage at least in part via AhR, JNK, or p38 activation and modulates the expression of oxidative stress-responsive genes such as cytoglobin to confer its anticancer action.

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“…More recently, Cygb was found to act as a tumor suppressor gene (23,24), and protect kidney fibroblasts under ischemic conditions (25), which are related to oxidative stress (25)(26)(27). Our hypothesis was that CYGB might protect neonatal rats from the damage associated with HI brain injury.…”

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confidence: 99%

Mechanisms of Neuroprotection from Hypoxia-Ischemia (HI) Brain Injury by Up-regulation of Cytoglobin (CYGB) in a Neonatal Rat Model

Tian

Yang

Xiao

et al. 2013

Journal of Biological Chemistry

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Background: Potential functions of cytoglobin (CYGB) in neonatal hypoxia-ischemia (HI) brain injury have not been reported. Results: Up-regulation of CYGB reduces HI injury and improves long term cognitive impairment after neonatal HI. Conclusion: CYGB exhibits neuroprotective effects, possibly through antioxidant and antiapoptotic functions as well as by stimulating angiogenesis. Significance: These results provide a novel target for developing a clinically relevant strategy for future studies.

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Cytoglobin, a Novel Member of the Globin Family, Protects Kidney Fibroblasts against Oxidative Stress under Ischemic Conditions

Cited by 52 publications

References 49 publications

Melanoma Transition Is Frequently Accompanied by a Loss of Cytoglobin Expression in Melanocytes: A Novel Expression Site of Cytoglobin

Melanoma Transition Is Frequently Accompanied by a Loss of Cytoglobin Expression in Melanocytes: A Novel Expression Site of Cytoglobin

Aryl Hydrocarbon Receptor Ligand 5F 203 Induces Oxidative Stress That Triggers DNA Damage in Human Breast Cancer Cells

Mechanisms of Neuroprotection from Hypoxia-Ischemia (HI) Brain Injury by Up-regulation of Cytoglobin (CYGB) in a Neonatal Rat Model

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