Multiple myeloma cell-derived IL-32γ increases the immunosuppressive function of macrophages by promoting indoleamine 2,3-dioxygenase (IDO) expression

Yan, Haimeng; Dong, Mengmeng; Liu, Xinling; Shen, Qiang; He, Donghua; Huang, Xi; Zhang, Enfan; Lin, Xuanru; Chen, Qingxiao; Guo, Xing; Chen, Jing; Zheng, Gaofeng; Wang, Gang; He, Jingsong; Yi, Qing; Zhang, Cai

doi:10.1016/j.canlet.2019.01.012

Cited by 41 publications

(23 citation statements)

References 42 publications

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“…Moreover, IL-32 as a proinflammatory factor has been demonstrated to promote angiogenesis (41). Our previous study showed that IL-32 was overexpressed in MM patients (42). In this study, we demonstrate that knockdown of KDM2A increases PFKFB3 level, which further increases IL-32 mRNA to enhance tube formation in HUVECs.…”

Section: Discussionsupporting

confidence: 57%

KDM2A Targets PFKFB3 for Ubiquitylation to Inhibit the Proliferation and Angiogenesis of Multiple Myeloma Cells

Liu

Wang

et al. 2021

Front. Oncol.

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The lysine demethylase KDM2A (also known as JHDM1A or FBXL11) demethylates histone H3 at lysine K36 which lead to epigenetic regulation of cell proliferation and tumorigenesis. However, many biological processes are mediated by KDM2A independently by its histone demethylation activity. In the present study, we aimed to characterize the functional significance of KDM2A in multiple myeloma (MM) disease progression. Specifically, we defined that one of the key enzymes of glycolysis PFKFB3 (6-phosphofructo-2-kinase) is ubiquitylated by KDM2A which suppresses MM cell proliferation. Previous study showed that KDM2A and PFKFB3 promoted angiogenesis in various tumor cells. We further reveal that KDM2A targets PFKFB3 for ubiquitination and degradation to inhibit angiogenesis. Several angiogenic cytokines are also downregulated in MM. Clinically, MM patients with low KDM2A and high PFKFB3 levels have shown worse prognosis. These results reveal a novel function of KDM2A through ubiquitin ligase activity by targeting PFKFB3 to induce proliferation, glycolysis and angiogenesis in MM cells. The data provides a new potential mechanism and strategy for MM treatment.

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Section: Discussionsupporting

confidence: 57%

KDM2A Targets PFKFB3 for Ubiquitylation to Inhibit the Proliferation and Angiogenesis of Multiple Myeloma Cells

Liu

Wang

et al. 2021

Front. Oncol.

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“…IDO-expressing macrophages interfered with T-cell activation, halting cell-cycle progression in the G1-phase. In multiple myeloma patients, tumor cells were described to secrete IL-32, triggering phosphorylation of STAT-3 and nuclear translocation of NFkB, subsequently inducing IDO expression in macrophages ( 55 ). Moreover, IDO + IL-32-educated macrophages suppressed proliferation of CD4 + T-cells when co-cultured in vitro .…”

Section: Ido In the Tumor Microenvironmentmentioning

confidence: 99%

IDO Expression in Cancer: Different Compartment, Different Functionality?

2020

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Indoleamine 2,3-dioxygenase 1 (IDO1) is a cytosolic haem-containing enzyme involved in the degradation of tryptophan to kynurenine. Although initially thought to be solely implicated in the modulation of innate immune responses during infection, subsequent discoveries demonstrated IDO1 as a mechanism of acquired immune tolerance. In cancer, IDO1 expression/activity has been observed in tumor cells as well as in the tumor-surrounding stroma, which is composed of endothelial cells, immune cells, fibroblasts, and mesenchymal cells. IDO1 expression/activity has also been reported in the peripheral blood. This manuscript reviews available data on IDO1 expression, mechanisms of its induction, and its function in cancer for each of these compartments. In-depth study of the biological function of IDO1 according to the expressing (tumor) cell can help to understand if and when IDO1 inhibition can play a role in cancer therapy.

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“…IL-32 is also expressed by regulatory or senescent/exhausted T cells in MM, but if/how this affects the function of the T-cells is not known 50, 51 . IL-32 is secreted from the MM cells and IL-32 in the BM microenvironment enhance osteoclast differentiation 15 , it can promote IL-6 production from stromal cells 52 and may generate immunosuppressive macrophages, 53 all factors that may lead to a more aggressive disease development.…”

Section: Discussionmentioning

confidence: 99%

IL-32 is a metabolic regulator promoting survival and proliferation of malignant plasma cells

Aass

Mjelle

Kastnes

et al. 2021

Preprint

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IL-32 is a non-classical cytokine expressed in cancers, inflammatory diseases and infections. IL-32 can have both extracellular and intracellular functions, and its receptor is not identified. We here demonstrate that endogenously expressed, intracellular IL-32 binds to components of the mitochondrial respiratory chain and promotes oxidative phosphorylation. Knocking out IL-32 in malignant plasma cells significantly reduced survival and proliferation in vitro and in vivo. High throughput transcriptomic and MS-metabolomic profiling of IL-32 KO cells revealed that loss of IL-32 leads to profound perturbations in metabolic pathways, with accumulation of lipids, pyruvate precursors and citrate, indicative of reduced mitochondrial function. IL-32 is expressed in a subgroup of multiple myeloma patients with an inferior prognosis. Primary myeloma cells expressing IL-32 were characterized by a plasma cell gene signature associated with immune activation, proliferation and oxidative phosphorylation. We propose a novel concept for regulation of metabolism by an intracellular cytokine and identify IL-32 as an endogenous growth and survival factor for malignant plasma cells. IL-32 is a potential prognostic biomarker and a treatment target in multiple myeloma.

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Multiple myeloma cell-derived IL-32γ increases the immunosuppressive function of macrophages by promoting indoleamine 2,3-dioxygenase (IDO) expression

Cited by 41 publications

References 42 publications

KDM2A Targets PFKFB3 for Ubiquitylation to Inhibit the Proliferation and Angiogenesis of Multiple Myeloma Cells

KDM2A Targets PFKFB3 for Ubiquitylation to Inhibit the Proliferation and Angiogenesis of Multiple Myeloma Cells

IDO Expression in Cancer: Different Compartment, Different Functionality?

IL-32 is a metabolic regulator promoting survival and proliferation of malignant plasma cells

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