Interleukin-32α promotes the proliferation of multiple myeloma cells by inducing production of IL-6 in bone marrow stromal cells

Lin, Xuanru; Yang, Li; Wang, Gang; Zi, Fuming; Yan, Haimeng; Guo, Xing; Chen, Jing; Chen, Qingxiao; Huang, Xi; Li, Yang; Zhang, Enfan; Wu, Wenjun; Yang, Yang; He, Donghua; He, Jingsong; Zhang, Cai

doi:10.18632/oncotarget.21611

Cited by 28 publications

(27 citation statements)

References 52 publications

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“…52 IL6 levels predict event-free survival in paediatric AML suggesting a mechanism of chemotherapy resistance 53 and IL32α promotes the proliferation of MM cells by inducing production of IL6 in bone marrow stromal cells. 54 Consistently, glioblastoma-derived IL6 induces immunosuppressive peripheral myeloid cell PD-L1 and promotes tumour growth 55 ; also, in the tumour microenvironment of upper-gastrointestinal cancers, IL6 mediates the cross-talk between tumour cells and pro-tumorigenic activated fibroblasts. 56 Similarly, IL8 is implicated in cancer cell growth, survival, angiogenesis and metastasis in several tumours.…”

Section: Discussionmentioning

confidence: 99%

“…Notably, IL6 is implicated in chemotherapy resistance by regulating the activity of anti‐apoptotic heat shock proteins and siltuximab, a chimeric mAb against IL6, is being tested in various clinical studies along with PI treatment . IL6 levels predict event‐free survival in paediatric AML suggesting a mechanism of chemotherapy resistance and IL32α promotes the proliferation of MM cells by inducing production of IL6 in bone marrow stromal cells . Consistently, glioblastoma‐derived IL6 induces immunosuppressive peripheral myeloid cell PD‐L1 and promotes tumour growth; also, in the tumour microenvironment of upper‐gastrointestinal cancers, IL6 mediates the cross‐talk between tumour cells and pro‐tumorigenic activated fibroblasts .…”

Section: Discussionmentioning

confidence: 99%

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Non‐lethal proteasome inhibition activates pro‐tumorigenic pathways in multiple myeloma cells

Skorda

Sklirou

Sakellaropoulos

et al. 2019

J Cellular Molecular Medi

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Multiple myeloma (MM) is a haematological malignancy being characterized by clonal plasma cell proliferation in the bone marrow. Targeting the proteasome with specific inhibitors (PIs) has been proven a promising therapeutic strategy and PIs have been approved for the treatment of MM and mantle‐cell lymphoma; yet, while outcome has improved, most patients inevitably relapse. As relapse refers to MM cells that survive therapy, we sought to identify the molecular responses induced in MM cells after non‐lethal proteasome inhibition. By using bortezomib (BTZ), epoxomicin (EPOX; a carfilzomib‐like PI) and three PIs, namely Rub999, PR671A and Rub1024 that target each of the three proteasome peptidases, we found that only BTZ and EPOX are toxic in MM cells at low concentrations. Phosphoproteomic profiling after treatment of MM cells with non‐lethal (IC10) doses of the PIs revealed inhibitor‐ and cell type‐specific readouts, being marked by the activation of tumorigenic STAT3 and STAT6. Consistently, cytokine/chemokine profiling revealed the increased secretion of immunosuppressive pro‐tumorigenic cytokines (IL6 and IL8), along with the inhibition of potent T cell chemoattractant chemokines (CXCL10). These findings indicate that MM cells that survive treatment with therapeutic PIs shape a pro‐tumorigenic immunosuppressive cellular and secretory bone marrow microenvironment that enables malignancy to relapse.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Non‐lethal proteasome inhibition activates pro‐tumorigenic pathways in multiple myeloma cells

Skorda

Sklirou

Sakellaropoulos

et al. 2019

J Cellular Molecular Medi

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“…66–69 Lastly, Pr-75 contains IL6R and IL32, which promotes osteoclastogenesis and stimulates BMSCs to produce IL6. 70,71 Taken together, the “double-hit” combination of amp 1q and t(4;14) bears signatures of a microenvironment that inactivates killing by cytotoxic lymphocytes, promotes formation of immuno-suppressive MDSCs and M2-polarized macrophages, and activates paracrine IL6 signaling. We note that the presence of both t(4;14) and amp 1q show synergistic activation of Pr-75 and Pr-134, such that patients harboring both abnormalities over-activate Pr-75 ( p<5 .…”

Section: Discussionmentioning

confidence: 99%

Genetic program activity delineates risk, relapse, and therapy responsiveness in Multiple Myeloma

Wall

Turkarslan

et al. 2020

Preprint

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38Despite recent advancements in the treatment of multiple myeloma (MM), nearly all patients 39 ultimately relapse and many become refractory to their previous therapies. Although many 40 therapies exist with diverse mechanisms of action, it is not yet clear how the differences in MM 41 biology across patients impacts the likelihood of success for existing therapies and those in the 42 pipeline. Therefore, we not only need the ability to predict which patients are at high risk for 43 disease progression, but also a means to understand the mechanisms underlying their risk. We 44 hypothesized that knowledge of the biological networks that give rise to MM, specifically the 45 transcriptional regulatory network (TRN) and the mechanisms by which mutations impact gene 46 regulation, would enable improved predictions of disease progression and actionable insights for 47 treatment. Here we present a method to infer TRNs from multi-omics data and apply it to the 48 generation of a MM TRN that links chromosomal abnormalities and somatic mutations to 49 downstream effects on gene expression via perturbation of transcriptional regulators. We find that 50 141 genetic programs underlie the disease and that the activity profile of these programs fall into 51 one of 25 distinct transcriptional states. These transcriptional signatures prove to be more 52 predictive of outcomes than do mutations and reveal plausible mechanisms for relapse, including 53 the establishment of an immuno-suppressive microenvironment. Moreover, we observe subtype-54 specific vulnerabilities to interventions with existing drugs and motivate the development of new 55 targeted therapies that appear especially promising for relapsed refractory MM. 56 57 Introduction 58 59 Multiple Myeloma (MM) is a cancer of malignant plasma cells in the bone marrow (BM) that has 60 a prevalence of approximately 86,000 new cases per year. 1 Several clinical subtypes of MM have 61 been established on the basis of characteristic cytogenetic features, including various 62 translocations, gain or loss of chromosomal arms, deletion of specific chromosomes, and 63 hyperdiploidy. 2-4 Accordingly, MM is a complex disease of great heterogeneity that exhibits64 subtype-specific drivers of progression. 5,6 Efforts to better characterize the biology and 65 therapeutic vulnerabilities of MM have increased exponentially in recent years, as can be seen 66 from the number of research articles, clinical trials, and public availability of matched genomic, 67 transcriptomic, and patient data. However, the myriad combinations of chromosomal aberrations 68 and somatic mutations, coupled with the complex dependence of MM progression on the BM 69 microenvironment, have precluded a mechanistic understanding of the disease on a patient-70 specific level. 72The 5-year survival rate of MM is approximately 50% 7 , which is nearly double what it was in the 73 late 1980s. 8 The reason for the improved outcomes is a series of therapeutic advances that 74 include the introduction of autologous stem cell t...

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“…Similarly, extracellular IL-32 has also been proposed to act as a mitogenic factor in breast cancer (43). Our group recently revealed that IL-32 promoted multiple myeloma cell growth through inducing the production of IL-6 in bone marrow stromal cells (44). Intracellular IL-32 also affects tumour growth.…”

Section: The Role Of Il-32 In Cancermentioning

confidence: 98%

Role of interleukin‑32 in cancer biology (Review)

Yan

Huang

et al. 2018

Oncol Lett

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Interleukin-32 (IL-32), a novel proinflammatory cytokine, is highly expressed in various cancer tissues and in established cancer cell lines. IL-32 has been revealed to serve a crucial role in human cancer development, including tumour initiation, proliferation and maintenance. The expression of IL-32 is regulated by numerous factors, including genetic variations, hypoxia and acidosis in the tumour microenvironment. Understanding the underlying mechanisms of IL-32 expression and its function are critical for the discovery of novel therapeutic strategies that target IL-32. This is a review of the current literature on the regulation and function of IL-32 in cancer progression, focusing on the molecular pathways linking IL-32 and tumour development.

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Interleukin-32α promotes the proliferation of multiple myeloma cells by inducing production of IL-6 in bone marrow stromal cells

Cited by 28 publications

References 52 publications

Non‐lethal proteasome inhibition activates pro‐tumorigenic pathways in multiple myeloma cells

Non‐lethal proteasome inhibition activates pro‐tumorigenic pathways in multiple myeloma cells

Genetic program activity delineates risk, relapse, and therapy responsiveness in Multiple Myeloma

Role of interleukin‑32 in cancer biology (Review)

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