Silencing Poly (ADP-Ribose) Glycohydrolase (PARG) Expression Inhibits Growth of Human Colon Cancer Cells In Vitro via PI3K/Akt/NFκ-B Pathway

Fauzee, Nilufer Jasmine Selimah; Qiao-zhuan, LI; Wang, Yalan; Perucho, Juan

doi:10.1007/s12253-011-9428-1

Cited by 19 publications

(22 citation statements)

References 36 publications

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“…cruzi persists in the host. It has been recently published that phosphorylated cytoplasmic IκBα is diminished in shRNA PARG Lovo cells and consequently the intranuclear expression of NF-κB p65 and the total protein expression of the latter are decreased [37]. Al-Halabi et al [38] have demonstrated that treatment with gallotannins inhibits NF-κB and slows the growth of human colon cancer xenografts.…”

Section: Discussionmentioning

confidence: 99%

Host Cell Poly(ADP-Ribose) Glycohydrolase Is Crucial for Trypanosoma cruzi Infection Cycle

et al. 2013

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Trypanosoma cruzi, etiological agent of Chagas’ disease, has a complex life cycle which involves the invasion of mammalian host cells, differentiation and intracellular replication. Here we report the first insights into the biological role of a poly(ADP-ribose) glycohydrolase in a trypanosomatid (TcPARG). In silico analysis of the TcPARG gene pointed out the conservation of key residues involved in the catalytic process and, by Western blot, we demonstrated that it is expressed in a life stage-dependant manner. Indirect immunofluorescence assays and electron microscopy using an anti-TcPARG antibody showed that this enzyme is localized in the nucleus independently of the presence of DNA damage or cell cycle stage. The addition of poly(ADP-ribose) glycohydrolase inhibitors ADP-HPD (adenosine diphosphate (hydroxymethyl) pyrrolidinediol) or DEA (6,9-diamino-2-ethoxyacridine lactate monohydrate) to the culture media, both at a 1 µM concentration, reduced in vitro epimastigote growth by 35% and 37% respectively, when compared to control cultures. We also showed that ADP-HPD 1 µM can lead to an alteration in the progression of the cell cycle in hydroxyurea synchronized cultures of T. cruzi epimastigotes. Outstandingly, here we demonstrate that the lack of poly(ADP-ribose) glycohydrolase activity in Vero and A549 host cells, achieved by chemical inhibition or iRNA, produces the reduction of the percentage of infected cells as well as the number of amastigotes per cell and trypomastigotes released, leading to a nearly complete abrogation of the infection process. We conclude that both, T. cruzi and the host, poly(ADP-ribose) glycohydrolase activities are important players in the life cycle of Trypanosoma cruzi, emerging as a promising therapeutic target for the treatment of Chagas’ disease.

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Section: Discussionmentioning

confidence: 99%

Host Cell Poly(ADP-Ribose) Glycohydrolase Is Crucial for Trypanosoma cruzi Infection Cycle

et al. 2013

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“…A strong case can be made for the importance of the biomedical implications of the inhibition of PARG in the field of cancer therapy. For example, the absence or inhibition of PARG has been shown to arrest the metastasis of cancer cells in the human colon and in murine models, the death of BRCA-2 tumor cells (487,488), and cell death of homologous repair-deficient tumor cells (489). PARG silencing led to a reduction in PARP expression and a decrease in signaling through the phosphatidylinositol (PI) 3-kinase/Akt pathway, mediated through a reduction in NF-B (487).…”

Section: Role Of Pargmentioning

confidence: 99%

Poly(ADP-Ribose) Polymerases in Host-Pathogen Interactions, Inflammation, and Immunity

Brady

Goel

Johnson

2019

Microbiol Mol Biol Rev

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SUMMARYThe literature review presented here details recent research involving members of the poly(ADP-ribose) polymerase (PARP) family of proteins. Among the 17 recognized members of the family, the human enzyme PARP1 is the most extensively studied, resulting in a number of known biological and metabolic roles. This review is focused on the roles played by PARP enzymes in host-pathogen interactions and in diseases with an associated inflammatory response. In mammalian cells, several PARPs have specific roles in the antiviral response; this is perhaps best illustrated by PARP13, also termed the zinc finger antiviral protein (ZAP). Plant stress responses and immunity are also regulated by poly(ADP-ribosyl)ation. PARPs promote inflammatory responses by stimulating proinflammatory signal transduction pathways that lead to the expression of cytokines and cell adhesion molecules. Hence, PARP inhibitors show promise in the treatment of inflammatory disorders and conditions with an inflammatory component, such as diabetes, arthritis, and stroke. These functions are correlated with the biophysical characteristics of PARP family enzymes. This work is important in providing a comprehensive understanding of the molecular basis of pathogenesis and host responses, as well as in the identification of inhibitors. This is important because the identification of inhibitors has been shown to be effective in arresting the progression of disease.

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“…Supporting these rationale for Parg inhibition being a novel approach for anti-cancer therapy are several reports indicating Parg inhibition has potent anti-tumor effects against cholangiocarinoma in vivo (Marienfeld et al, 2003), and in vitro data showing growth inhibitory activity of Parg inhibition or knockdown in multiple types of cancer (Fauzee et al, 2012; Feng et al, 2012; Li et al, 2012; Pan et al, 2012). Now that the crystal structure of Parg has been solved (Slade et al, 2011; Kim et al, 2012), there is a clear need to develop specific inhibitors of this enzyme and test their efficacy as anti-cancer therapeutics.…”

Section: Clinical Modulation Of the Poly(adp)ribose Pathway: Future Pmentioning

confidence: 93%

Is There an Epigenetic Component Underlying the Resistance of Triple-Negative Breast Cancers to Parp Inhibitors?

2012

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Poly(ADP-ribose) polymerase (Parp) is an enzyme responsible for catalyzing post-translational modifications through the addition of poly(ADP-ribose) chains (known as PARylation). Modification by PARylation modulates numerous cellular processes including transcription, chromatin remodeling, apoptosis, and DNA damage repair. In particular, the role of Parp activation in response to DNA damage has been intensely studied. Tumors bearing mutations of the breast cancer susceptibility genes, Brca1/2, are prone to DNA breakages whose restoration into functional double-strand DNA is Parp dependent. This concept has been exploited therapeutically in Brca mutated breast and ovarian tumors, where acute sensitivity to Parp inhibitors is observed. Based on in vitro and clinical studies it remains unclear to what extent Parp inhibitors can be utilized beyond treating Brca mutated tumors. This review will focus on the often overlooked roles of PARylation in chromatin remodeling, epigenetics, and transcription to explain why some cancers may be unresponsive to Parp inhibition. We predict that understanding the impact of PARylation on gene expression will lead to alternative approaches to manipulate the Parp pathway for therapeutic benefit.

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Silencing Poly (ADP-Ribose) Glycohydrolase (PARG) Expression Inhibits Growth of Human Colon Cancer Cells In Vitro via PI3K/Akt/NFκ-B Pathway

Cited by 19 publications

References 36 publications

Host Cell Poly(ADP-Ribose) Glycohydrolase Is Crucial for Trypanosoma cruzi Infection Cycle

Host Cell Poly(ADP-Ribose) Glycohydrolase Is Crucial for Trypanosoma cruzi Infection Cycle

Poly(ADP-Ribose) Polymerases in Host-Pathogen Interactions, Inflammation, and Immunity

Is There an Epigenetic Component Underlying the Resistance of Triple-Negative Breast Cancers to Parp Inhibitors?

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