Indoleamine 2,3-dioxygenase mediates immune-independent human tumor cell resistance to olaparib, gamma radiation, and cisplatin

Vareki, Saman Maleki; Rytelewski, Mateusz; Figueredo, René; Chen, Di; Ferguson, Peter J.; Vincent, Mark; Min, Wei‐Ping; Zheng, Xiufen; Koropatnick, James

doi:10.18632/oncotarget.1916

Cited by 40 publications

(33 citation statements)

References 45 publications

(60 reference statements)

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“…IDO1 expression correlates with decreased proliferation of immune cells [13, 14] and its silencing provided the opposite outcome [5]. Because IDO2 shares the same enzymatic function, we investigated the effect of IDO2 on B16-BL6 cell proliferation using an MTT assay.…”

Section: Resultsmentioning

confidence: 99%

“…Both IDO1 and IDO2 are known immunosuppressive molecules, and their immune suppressive function has been investigated both in vivo and in vitro . A recent study reported by the Koropatnick group shows that IDO1, expressed in tumor cells, presents immune-independent function in response to chemotherapeutic and radioactive drugs [5]. We recently observed that cells in the invasive melanoma cell line, B16-BL6, highly express IDO2 whereas the less invasive melanoma cell line, B16F10, had limited expression of IDO2 in the absence of interferon-gamma (IFN-γ) induction.…”

Section: Introductionmentioning

confidence: 99%

“…Inhibition of NAD+ formation leads to cell apoptosis [10, 11]. Knocking down IDO1 using siRNA-reduced NAD+ generation, leads to enhanced sensitivity of tumor cells to chemotherapeutic drugs [5]. It is unknown, however, if downregulation of IDO2 expression can induce cell apoptosis/death by suppressing NAD+.…”

Section: Introductionmentioning

confidence: 99%

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Gene silencing of indoleamine 2,3-dioxygenase 2 in melanoma cells induces apoptosis through the suppression of NAD+ and inhibits in vivo tumor growth

et al. 2016

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Indoleamine 2,3-dioxygenase 2 (IDO2) is a newly discovered enzyme that catalyzes the initial and rate-limiting step in the degradation of tryptophan. As a homologous protein of IDO1, IDO2 plays an inhibitory role in T cell proliferation, and it is essential for regulatory T cell (Treg) generation in healthy conditions. Little is known about the immune-independent functions of IDO2 relevant to its specific contributions to physiology and pathophysiology in cancer cells. The purpose of this study was to assess the impact of IDO2 gene silencing as a way to inhibit B16-BL6 cancer cells in a murine model. Here, for the first time, we show that knockdown of IDO2 using small interfering RNA (siRNA) inhibits cancer cell proliferation, arrests cell cycle in G1, induces greater cell apoptosis, and reduces cell migration in vitro. Knockdown of IDO2 decreased the generation of nicotinamide adenine dinucleotide (NAD+) while increasing the generation of reactive oxygen species (ROS). We further demonstrate that cell apoptosis, induced by IDO2 downregulation, can be weakened by addition of exogenous NAD+, suggesting a novel mechanism by which IDO2 promotes tumor growth through its metabolite product NAD+. In addition to in vitro findings, we also demonstrate that IDO2 silencing in tumor cells using short hairpin RNA (shRNA) delayed tumor formation and arrested tumor growth in vivo. In conclusion, this study demonstrates a new non-immune-associated mechanism of IDO2 in vitro and IDO2 expression in B16-BL6 cells contributes to cancer development and progression. Our research provides evidence of a novel target for gene silencing that has the potential to enhance cancer therapy.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Gene silencing of indoleamine 2,3-dioxygenase 2 in melanoma cells induces apoptosis through the suppression of NAD+ and inhibits in vivo tumor growth

et al. 2016

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“…This may serve as an immune-escape mechanism (which is the focus of this review), or in some cases may confer some non-immune survival advantage on the tumors [40, 41]. IDO can also be expressed in tumor-associated cells such as DCs or endothelial cells.…”

Section: Physiologic Ido Induction At Sites Of Inflammationmentioning

confidence: 99%

IDO in the Tumor Microenvironment: Inflammation, Counter-Regulation, and Tolerance

Munn

Mellor

2016

Trends in Immunology

774

662

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Indoleamine 2,3-dioxygenase (IDO) has immunoregulatory roles associated tryptophan metabolism. These include counter-regulation (controlling inflammation) and acquired tolerance in T cells. Recent findings reveal that IDO can be triggered by innate responses during tumorigenesis, and also by attempted T cell activation, either spontaneous or due to immunotherapy. Here we review the current understanding of mechanisms by which IDO participates in the control of inflammation and in peripheral tolerance. Focusing on the tumor microenvironment, we examine the role of IDO in response to apoptotic cells and the impact of IDO on Treg cell function. We discuss how the counter-regulatory and tolerogenic functions of IDO can be targeted for cancer immunotherapy and present an overview of the current clinical progress in this area.

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“…At 48 h after transfection, PIV3 was added at an MOI of 2; cell lysates were made after another 24 h and analyzed by immunoblotting. A549 cell clone 2-18, stably expressing lentiviral short hairpin RNA (shRNA) against IDO, and control cell clone NC-3, expressing scrambled shRNA (NC-3), have been described in detail previously (20). These cells were treated with IFN-␥ and infected with PIV3 as described above.…”

Section: Cells Virus and Ifnmentioning

confidence: 99%

Identification of Interferon-Stimulated Gene Proteins That Inhibit Human Parainfluenza Virus Type 3

Rabbani

Ribaudo

Guo

et al. 2016

J Virol

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A major arm of cellular innate immunity is type I interferon (IFN), represented by IFN-␣ and IFN-␤. Type I IFN transcriptionally induces a large number of cellular genes, collectively known as IFN-stimulated gene (ISG) proteins, which act as antivirals. The IFIT (interferon-induced proteins with tetratricopeptide repeats) family proteins constitute a major subclass of ISG proteins and are characterized by multiple tetratricopeptide repeats (TPRs). In this study, we have interrogated IFIT proteins for the ability to inhibit the growth of human parainfluenza virus type 3 (PIV3), a nonsegmented negative-strand RNA virus of the Paramyxoviridae family and a major cause of respiratory disease in children. We found that IFIT1 significantly inhibited PIV3, whereas IFIT2, IFIT3, and IFIT5 were less effective or not at all. In further screening a set of ISG proteins we discovered that several other such proteins also inhibited PIV3, including IFITM1, IDO (indoleamine 2,3-dioxygenase), PKR (protein kinase, RNA activated), and viperin (virus inhibitory protein, endoplasmic reticulum associated, interferon inducible)/Cig5. The antiviral effect of IDO, the enzyme that catalyzes the first step of tryptophan degradation, could be counteracted by tryptophan. These results advance our knowledge of diverse ISG proteins functioning as antivirals and may provide novel approaches against PIV3. IMPORTANCE The innate immunity of the host, typified by interferon (IFN), is a major antiviral defense. IFN inhibits virus growth by inducing a large number of IFN-stimulated gene (ISG) proteins, several of which have been shown to have specific antiviral functions.Parainfluenza virus type 3 (PIV3) is major pathogen of children, and no reliable vaccine or specific antiviral against it currently exists. In this article, we report several ISG proteins that strongly inhibit PIV3 growth, the use of which may allow a better antiviral regimen targeting PIV3. P arainfluenza virus type 3 (PIV3) is a nonsegmented, negativestrand RNA virus belonging to the Paramyxoviridae family and a major cause of lower respiratory tract infection in humans and cattle (1-3). Human PIV3 is a particularly serious pathogen in young children, second in clinic importance only to respiratory syncytial virus (RSV), another member of the same family (3). There is currently no specific treatment or approved vaccine for PIV3. However, RNA viruses in general, and paramyxoviruses in particular, induce type I interferon (IFN), a major arm of host innate immunity, mainly by activating a cytoplasmic RNA helicase of the RIG-I family, which is followed by a signaling cascade ultimately leading to transcriptional induction of IFN genes (4-6). Early reports showed that PIV3 is highly sensitive to IFN (7), suggesting that this natural antiviral mechanism holds the potential to be harnessed. Type I IFN by itself has no antiviral activity, but upon binding to its cognate receptor on the cell surface, it triggers the so-called IFN response pathway, in which transcription factors STAT...

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Indoleamine 2,3-dioxygenase mediates immune-independent human tumor cell resistance to olaparib, gamma radiation, and cisplatin

Cited by 40 publications

References 45 publications

Gene silencing of indoleamine 2,3-dioxygenase 2 in melanoma cells induces apoptosis through the suppression of NAD+ and inhibits in vivo tumor growth

Gene silencing of indoleamine 2,3-dioxygenase 2 in melanoma cells induces apoptosis through the suppression of NAD+ and inhibits in vivo tumor growth

IDO in the Tumor Microenvironment: Inflammation, Counter-Regulation, and Tolerance

Identification of Interferon-Stimulated Gene Proteins That Inhibit Human Parainfluenza Virus Type 3

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