IL-17A Increases Multiple Myeloma Cell Viability by Positively Regulating Syk Expression

Wang, Shunye; Ma, Yanan; Wang, Xudong; Jiang, Jie; Zhang, Chenglu; Wang, Xinfeng; Jiang, Yijing; Huang, Hongming; Hong, Liu

doi:10.1016/j.tranon.2019.04.023

Cited by 17 publications

(10 citation statements)

References 30 publications

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“…Other cytokines implicated in the pathobiology of MM include CSF-1, IL-6, IL-17, IL-21, IL-23, VEGF, growth differentiating factor 15, IGF-1, and myeloma-cell-secreted type 1 IFN [ 5 , 11 , 79 , 80 , 81 ]. CSF1 is the main driver of differentiation of M1 macrophages into immunosuppressive M2 macrophages.…”

Section: Targeting Transforming Growth Factor Beta (Tgf-β) Signaling and Syk-pi3k-akt Pathwaymentioning

confidence: 99%

Overcoming the Immunosuppressive Tumor Microenvironment in Multiple Myeloma

Uckun

2021

Cancers

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SeverFigurel cellular elements of the bone marrow (BM) microenvironment in multiple myeloma (MM) patients contribute to the immune evasion, proliferation, and drug resistance of MM cells, including myeloid-derived suppressor cells (MDSCs), tumor-associated M2-like, “alternatively activated” macrophages, CD38+ regulatory B-cells (Bregs), and regulatory T-cells (Tregs). These immunosuppressive elements in bidirectional and multi-directional crosstalk with each other inhibit both memory and cytotoxic effector T-cell populations as well as natural killer (NK) cells. Immunomodulatory imide drugs (IMiDs), protease inhibitors (PI), monoclonal antibodies (MoAb), adoptive T-cell/NK cell therapy, and inhibitors of anti-apoptotic signaling pathways have emerged as promising therapeutic platforms that can be employed in various combinations as part of a rationally designed immunomodulatory strategy against an immunosuppressive tumor microenvironment (TME) in MM. These platforms provide the foundation for a new therapeutic paradigm for achieving improved survival of high-risk newly diagnosed as well as relapsed/refractory MM patients. Here we review the scientific rationale and clinical proof of concept for each of these platforms.

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Section: Targeting Transforming Growth Factor Beta (Tgf-β) Signaling and Syk-pi3k-akt Pathwaymentioning

confidence: 99%

Overcoming the Immunosuppressive Tumor Microenvironment in Multiple Myeloma

Uckun

2021

Cancers

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“…Alternatively, most BCR-related kinases are known to play a variety of different functions depending on their cellular context. Syk, for example, also orchestrates TNFα and NF-κB signaling in MM and other, non-hematological cells [ 55 , 56 , 57 ]. By inhibiting Syk, GPX4-inhibitor RSL3 potentially triggers MM cell death through inactivation of these two oncogenic pathways.…”

Section: Discussionmentioning

confidence: 99%

Phosphocatalytic Kinome Activity Profiling of Apoptotic and Ferroptotic Agents in Multiple Myeloma Cells

Logie

Pérez-Novo

Driesen

et al. 2021

IJMS

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Through phosphorylation of their substrate proteins, protein kinases are crucial for transducing cellular signals and orchestrating biological processes, including cell death and survival. Recent studies have revealed that kinases are involved in ferroptosis, an iron-dependent mode of cell death associated with toxic lipid peroxidation. Given that ferroptosis is being explored as an alternative strategy to eliminate apoptosis-resistant tumor cells, further characterization of ferroptosis-dependent kinase changes might aid in identifying novel druggable targets for protein kinase inhibitors in the context of cancer treatment. To this end, we performed a phosphopeptidome based kinase activity profiling of glucocorticoid-resistant multiple myeloma cells treated with either the apoptosis inducer staurosporine (STS) or ferroptosis inducer RSL3 and compared their kinome activity signatures. Our data demonstrate that both cell death mechanisms inhibit the activity of kinases classified into the CMGC and AGC families, with STS showing a broader spectrum of serine/threonine kinase inhibition. In contrast, RSL3 targets a significant number of tyrosine kinases, including key players of the B-cell receptor signaling pathway. Remarkably, additional kinase profiling of the anti-cancer agent withaferin A revealed considerable overlap with ferroptosis and apoptosis kinome activity, explaining why withaferin A can induce mixed ferroptotic and apoptotic cell death features. Altogether, we show that apoptotic and ferroptotic cell death induce different kinase signaling changes and that kinome profiling might become a valid approach to identify cell death chemosensitization modalities of novel anti-cancer agents.

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“…In the present study, the IL-17A level in serum was found to be significantly higher in MM patients, and highest in those refractory to bortezomib. IL-17A has previously been found to be highly expressed in MM patients and to be able to induce MM cell viability [27], as well as to regulate osteoclast formation and activation [28]. It also promotes myeloma cell growth, inhibits immune function in MM through IL-17 receptor activity, and enhances adhesion to bone marrow stromal cells.…”

Section: Discussionmentioning

confidence: 99%

Cytokine and Chemokine Profile in Patients with Multiple Myeloma Treated with Bortezomib

Robak

Węgłowska²,

Dróźdż

et al. 2020

Mediators of Inflammation

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The aim of the study was to determine the levels of selected cytokines and chemokines in the serum of multiple myeloma (MM) patients treated with bortezomib-based regimens. A total of 71 MM patients were examined: 41 with primary refractory disease (17) or early relapse (28), and 30 who were bortezomib sensitive with no progression for at least six months. Patients who demonstrated CR or PR after bortezomib-based therapies longer than six months after treatment discontinuation were designated bortezomib sensitive. Serum cytokine levels were assayed with Bio-Rad Bio-Plex Pro Human Cytokine 27-Plex Assay on the MAGPIX Multiplex Reader and the Bio-Plex® 200 System (Bio-Rad). Higher levels of MIP-1α and lower levels of MIP-1β and IL-9 were associated with better responses to bortezomib-based treatment, and higher levels of IL-1ra and IL-8 were associated with bone involvement. MCP-1 was elevated in patients with hemoglobin<10 g/dl compared to those without anemia. The levels of IL-8, MIP-1α, and TNF-α were significantly higher in patients with renal insufficiency. Only MIP-1α was elevated in patients with hypercalcemia compared to patients with normal calcium levels. In conclusion, distinct cytokines are involved in the pathogenesis of MM and may play a prominent role in the prediction of treatment response. However, a single measurement of serum cytokines should be interpreted with caution and further studies are needed.

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IL-17A Increases Multiple Myeloma Cell Viability by Positively Regulating Syk Expression

Cited by 17 publications

References 30 publications

Overcoming the Immunosuppressive Tumor Microenvironment in Multiple Myeloma

Overcoming the Immunosuppressive Tumor Microenvironment in Multiple Myeloma

Phosphocatalytic Kinome Activity Profiling of Apoptotic and Ferroptotic Agents in Multiple Myeloma Cells

Cytokine and Chemokine Profile in Patients with Multiple Myeloma Treated with Bortezomib

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