Redox Regulation of Pancreatic Cancer Cell Growth: Role of Glutathione Peroxidase in the Suppression of the Malignant Phenotype

Liu, Jingru; Hinkhouse, Marilyn M.; Sun, Wenqing; Weydert, Christine J.; Ritchie, Justine M.; Oberley, Larry W.; Cullen, Joseph J.

doi:10.1089/104303404322886093

Cited by 105 publications

(75 citation statements)

References 27 publications

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“…Both CLIC1 and CLIC4 are subject to redox regulation with major structural rearrangements and functional activities dependent on redox state (33,34). Because cancer cells frequently exhibit altered redox regulation (35,36), this control of CLIC4 subcellular localization should be considered.…”

Section: Discussionmentioning

confidence: 99%

Reciprocal Modifications of CLIC4 in Tumor Epithelium and Stroma Mark Malignant Progression of Multiple Human Cancers

Suh

Crutchley

Koochek

et al. 2007

Clinical Cancer Research

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Purpose: CLIC4, a member of a family of intracellular chloride channels, is regulated by p53, c-Myc, and tumor necrosis factor-a. Regulation by factors involved in cancer pathogenesis, together with the previously shown proapoptotic activity of CLIC4, suggests that the protein may have a tumor suppressor function. To address this possibility, we characterized the expression profile, subcellular localization, and gene integrity of CLIC4 in human cancers and determined the functional consequences of CLIC4 expression in tumor epithelium and stromal cells. Experimental Design: CLIC4 expression profiles were analyzed by genomics, proteomics, bioinformatics, and tissue microarrays. CLIC4 expression, as a consequence of crosstalk between stroma and epithelium, was tested in vitro by coculture of breast epithelial tumor cells and normal fibroblasts, and the functional consequences of CLIC4 expression was tested in vivo in xenografts of human breast tumor cell lines reconstituted with CLIC4 or mixed with fibroblasts that overexpress CLIC4 transgenically. Results: In cDNA arrays of matched human normal and tumor tissues, CLIC4 expression was reduced in renal, ovarian, and breast cancers. However, CLIC4 protein levels were variable in tumor lysate arrays. Transcript sequences of CLIC4 from the human expressed sequence tag database and manual sequencing of cDNA from 60 human cancer cell lines (NCI60) failed to reveal deletion or mutations in the CLIC4 gene. On matched tissue arrays, CLIC4 was predominantly nuclear in normal human epithelial tissues but not cancers.With advancing malignant progression, CLIC4 staining became undetectable in tumor cells, but expression increased in stromal cells coincident with up-regulation of a-smooth muscle actin, suggesting that CLIC4 is up-regulated in myofibroblasts. Coculture of cancer cells and fibroblasts induced the expression of both CLIC4 and a-smooth muscle actin in fibroblasts adjacent to tumor nests. Introduction of CLIC4 or nuclear targeted CLIC4 via adenovirus into human breast cancer xenografts inhibited tumor growth, whereas overexpression of CLIC4 in stromal cells of xenografts enhanced tumor growth. Conclusion: Loss of CLIC4 in tumor cells and gain in tumor stroma is common to many human cancers and marks malignant progression. Up-regulation of CLIC4 in tumor stroma is coincident with myofibroblast conversion, generally a poor prognostic indicator. Reactivation and restoration of CLIC4 in tumor cells or the converse in tumor stromal cells could provide a novel approach to inhibit tumor growth.

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Section: Discussionmentioning

confidence: 99%

Reciprocal Modifications of CLIC4 in Tumor Epithelium and Stroma Mark Malignant Progression of Multiple Human Cancers

Suh

Crutchley

Koochek

et al. 2007

Clinical Cancer Research

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“…In that study, hepatocellular apoptosis was decreased with a resultant increase in dysplastic hepatocytes and these phenotypic changes were likely related to p53 expression. Furthermore, increased ROS activity has been linked to malignant transformation [19] which may be related to cytokine receptor profiles and resistance to apoptosis [20] or to decreased expression of antioxidants [8,21]. In addition to decreasing responsiveness to apoptosis, increased ROS may result in negative regulatory changes in the cell cycle and alter the balance between proliferation and apoptosis [22].…”

Section: Discussionmentioning

confidence: 99%

Basal reactive oxygen species determine the susceptibility to apoptosis in cirrhotic hepatocytes

Raval

Lyman

Nitta

et al. 2006

Free Radical Biology and Medicine

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Hepatocytes from cirrhotic murine livers exhibit increased basal ROS activity and resistance to TGFβ-induced apoptosis, yet when ROS levels are decreased by antioxidant pretreatment, these cells recover susceptibility to apoptotic stimuli. To further study these redox events, hepatocytes from cirrhotic murine livers were pretreated with various antioxidants prior to TGFβ treatment and the ROS activity, apoptotic response, and mitochondrial ROS generation were assessed. In addition, normal hepatocytes were treated with low-dose H 2 O 2 and ROS and apoptotic responses determined. Treatment of cirrhotic hepatocytes with various antioxidants decreased basal ROS and rendered them susceptible to apoptosis. Examination of normal hepatocytes by confocal microscopy demonstrated co-localization of ROS activity and respiring mitochondria. Basal assessment of cirrhotic hepatocytes showed non-focal ROS activity that was abolished by antioxidants. After pretreatment with an adenovirus expressing MnSOD, basal cirrhotic hepatocyte ROS was decreased and TGFβ-induced co-localization of ROS and mitochondrial respiration was present. Treatment of normal hepatocytes with H 2 O 2 resulted in a sustained increase in ROS and resistance to TGFβ apoptosis that was reversed when these cells were pretreated with an antioxidant. In conclusion, cirrhotic hepatocytes have a non-focal distribution of ROS. However, normal and cirrhotic hepatocytes exhibit mitochondrial localization of ROS that is necessary for apoptosis.

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“…GPx-1 is classified as an antioxidant enzyme and exerts its role to prevent the initiation of cancer by ROS-mediated DNA damage. Previous studies have suggested that GPx-1 is altered in several types of cancer cells (11,12) and overexpression of GPx-1 shows antitumorigenic effect by eliminating oxidants (13). On the other hand, GPx-1 also increases tumorigenesis in transformed cells by limiting apoptotic mechanisms (14,15).…”

Section: Introductionmentioning

confidence: 99%

Transforming growth factor-β1 induces glutathione peroxidase-1 and protects from H2O2-induced cell death in colon cancer cells via the Smad2/ERK1/2/HIF-1α pathway

et al. 2012

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Abstract.Recent studies have shown that transforming growth factor-β1 (TGF-β1) signaling plays important roles in the redox system in benign and malignant cells. Whether TGF-β mediates an antioxidative damage response in colorectal cancer cells is largely unknown. Herein, using the human colorectal cancer cell lines we found that TGF-β1 induced glutathione peroxidase-1 (GPx-1) expression and enzyme activity, and that the upregulation of GPx-1 by TGF-β1 could protect colorectal cell lines from H 2 O 2 -induced oxidation damage. Further, we used loss-and gain-function approaches to elucidate the underlying mechanism and found that TGF-β1 induced GPx-1 through activation of the TGF-β receptor type I (TGF-βRI)/ Smad2/extracellular-signal-regulated kinase 1/2 (ERK1/2)/ hypoxia-inducible factor-1α (HIF-1α) signaling pathway. This cascade could be blocked by the TGF-βRI inhibitor or ERK1/2 inhibitor. Taken together, our data demonstrated that TGF-β1 induced GPx-1 expression and enzymatic activity via the TGF-βRI/Smad2/ERK1/2/HIF-1α signaling pathway, suggesting a novel antioxidative protective function of TGF-β1 in colorectal cancer cells. IntroductionTransforming growth factor-β (TGF-β) is a multifunctional cytokine and plays very important roles in development, differentiation and in maintaining homeostasis in almost all cell types and tissues (1). TGF-β functions via transmembrane serine/threonine kinase receptors, the type I and type II receptors (TGF-βRI and TGF-βRII) (2) and intracellular Smad transcriptional regulators (3). Increasing evidence has indicated that TGF-β is involved in the redox system in benign and tumor cells, in terms of that TGF-β can induce production of reactive oxygen species (ROS) which stimulates proliferation, invasion, migration and angiogenesis and evade apoptosis in cancer cells (4). TGF-β1 can stimulate a rapid increase in ROS generation to induce kidney myofibroblast activation and matrix synthesis (5). In renal tubular epithelial cells, TGF-β1 induces cellular ROS and mediates the epithelial-mesenchymal transition (EMT). All these effects can be abrogated by antioxidants (6). Low levels of ROS play a very important role in keeping normal cell proliferation by regulating cellular signaling. A great body of evidence indicates that production of ROS is increased in cancer cells and elevated ROS may facilitate tumor cell growth (7). However, a higher level of ROS may act reversely to induce an apoptotic response of tumor cells. Moderate ROS levels provide tumor cells with the advantage to maintain survival. Glutathione peroxidases (GPxs) are of the most important antioxidative enzyme families which can modulate cellular ROS levels to keep the redox balance in tumor cells.GPx-1 is the first identified selenoprotein and is expressed in most cells (8-10). GPx-1 is classified as an antioxidant enzyme and exerts its role to prevent the initiation of cancer by ROS-mediated DNA damage. Previous studies have suggested that GPx-1 is altered in several types of cancer cells (11,12) and overexpres...

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Redox Regulation of Pancreatic Cancer Cell Growth: Role of Glutathione Peroxidase in the Suppression of the Malignant Phenotype

Cited by 105 publications

References 27 publications

Reciprocal Modifications of CLIC4 in Tumor Epithelium and Stroma Mark Malignant Progression of Multiple Human Cancers

Reciprocal Modifications of CLIC4 in Tumor Epithelium and Stroma Mark Malignant Progression of Multiple Human Cancers

Basal reactive oxygen species determine the susceptibility to apoptosis in cirrhotic hepatocytes

Transforming growth factor-β1 induces glutathione peroxidase-1 and protects from H2O2-induced cell death in colon cancer cells via the Smad2/ERK1/2/HIF-1α pathway

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