JMJD3-regulated expression of IL-6 is involved in the proliferation and chemosensitivity of acute myeloid leukemia cells

Xu, Xiaojun; Ye, Yongbin; Wang, Xiaobo; Lü, Bo; Guo, Ziwen; Wu, She–Ching

doi:10.1515/hsz-2020-0345

Cited by 8 publications

(4 citation statements)

References 42 publications

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“…Fittingly, Mallaney et al reported that a complete loss of Kdm6b severely impaired HSCs stem cell self-renewal and prolonged survival of MLL-AF9 leukemic mice [ 63 ]. Likewise, KDM6B knockdown re-sensitized AML cell lines to daunorubicin and cytarabine by downregulation of IL6 [ 64 ]. Together, these studies clearly suggest a potential for KDM6B as a drug target in MDS and AML.…”

Section: Resultsmentioning

confidence: 99%

The Cross Marks the Spot: The Emerging Role of JmjC Domain-Containing Proteins in Myeloid Malignancies

2021

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Histone methylation tightly regulates chromatin accessibility, transcription, proliferation, and cell differentiation, and its perturbation contributes to oncogenic reprogramming of cells. In particular, many myeloid malignancies show evidence of epigenetic dysregulation. Jumonji C (JmjC) domain-containing proteins comprise a large and diverse group of histone demethylases (KDMs), which remove methyl groups from lysines in histone tails and other proteins. Cumulating evidence suggests an emerging role for these demethylases in myeloid malignancies, rendering them attractive targets for drug interventions. In this review, we summarize the known functions of Jumonji C (JmjC) domain-containing proteins in myeloid malignancies. We highlight challenges in understanding the context-dependent mechanisms of these proteins and explore potential future pharmacological targeting.

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Section: Resultsmentioning

confidence: 99%

The Cross Marks the Spot: The Emerging Role of JmjC Domain-Containing Proteins in Myeloid Malignancies

2021

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“…Previous studies revealed the pivotal role of the cytokine IL-6 in the process of chemotherapeutic resistance [ 17 – 19 ]. However, no systematic mechanistic investigation has been conducted from a phosphoproteomic perspective.…”

Section: Discussionmentioning

confidence: 99%

Quantitative phosphoproteomic analysis reveals chemoresistance-related proteins and signaling pathways induced by rhIL-6 in human osteosarcoma cells

Zhang

Wang

et al. 2021

Cancer Cell Int

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Background IL-6 plays a pivotal role in resistance to chemotherapeutics, including lobaplatin. However, the underlying mechanisms are still unclear. This study was to investigate the changes in phosphoproteins and their related signaling pathways in the process of IL-6-induced chemoresistance to lobaplain in osteosarcoma cells. Methods We performed a quantitative phosphoproteomic analysis of the response of SaOS-2 osteosarcoma cells to recombinant human IL-6 (rhIL-6) intervention prior to lobaplatin treatment. The cells were divided into the control group (Con), the lobaplatin group (Lob), and the rhIL-6-and-lobaplatin group (IL-6). Three biological replicates of each group were included. The differentially expressed phosphoproteins were subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Netphos 3.1 was used for the prediction of kinases, and STRING was used for the visualization of protein–protein interactions. The conserved motifs surrounding the phosphorylated residues were analyzed using the motif-x algorithm. Western blot analysis was performed to verify the differential expression of p-FLNC, its predicted kinase and the related signaling pathway. The results of the bioinformatic analysis were validated by immunohistochemical staining of clinical specimens. Results In total, 3373 proteins and 12,183 peptides, including 3232 phosphorylated proteins and 11,358 phosphorylated peptides, were identified and quantified. Twenty-three significantly differentially expressed phosphoproteins were identified in the comparison between the IL-6 and Lob groups, and p-FLNC ranked second among these phosphoproteins. GO and KEGG analyses revealed the pivotal role of mitogen-activated protein kinase signaling in drug resistance induced by rhIL-6. Four motifs, namely, -SPxxK-, -RxxSP-, -SP-, and -SPK-, demonstrated higher expression in the IL-6 group than in the Lob group. The western blot analysis results verified the higher expression of p-FLNC, AKT1, and p-ERK and the lower expression of p-JNK in the IL-6 group than in the Con and Lob groups. The immunohistochemical staining results showed that p-FLNC, AKT1 and p-ERK1/2 were highly expressed in platinum-resistant clinical specimens but weakly expressed in platinum-sensitive specimens, and platinum-resistant osteosarcoma specimens demonstrated weak expression of p-JNK. Conclusions This phosphoproteomic study is the first to reveal the signature associated with rhIL-6 intervention before lobaplatin treatment in human osteosarcoma cells. p-FLNC, AKT1, and MAPK signaling contributes to resistance to lobaplatin in osteosarcoma SaOS-2 cells and may represent molecular targets to overcome osteosarcoma chemoresistance.

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“…Studies have shown that elevated levels of serum IL-6 is positively correlated with worse clinical outcomes in patients with different types of cancer, including leukemia [54,55]. IL-6 also plays a key role in the chemoresistance of malignancies [56][57][58]. Based on these findings we checked the effect of our new benzofuran derivatives on IL-6 secretion by K562 cells.…”

Section: Inhibition Of Il-6 Releasementioning

confidence: 97%

New Derivatives of 1-(3-Methyl-1-Benzofuran-2-yl)Ethan-1-one: Synthesis and Preliminary Studies of Biological Activity

Napiórkowska,

Kumaravel,

Amboo Mahentheran

et al. 2024

IJMS

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A set of nine derivatives, including five brominated compounds, was synthesized and the structures of these novel compounds were confirmed using 1H and 13C NMR as well as ESI MS spectra. These compounds were tested on four different cancer cell lines, chronic myelogenous leukemia (K562), prostate cancer (PC3), colon cancer (SW620), human kidney cancer (Caki 1), and on healthy human keratocytes (HaCaT). MTT results reveal that two newly developed derivatives (6 and 8) exhibit selective action towards K562 cells and no toxic effect in HaCat cells. The biological activity of these two most promising compounds was evaluated by trypan blue assay, reactive oxygen species generation, and IL-6 secretion. To investigate the proapoptotic activity of selected compounds, the two following types of tests were performed: Annexin V Apoptosis Detection Kit I and Caspase-Glo 3/7 assay. The studies of the mechanism showed that both compounds have pro-oxidative effects and increase reactive oxygen species in cancer cells, especially at 12 h incubation. Through the Caspase-Glo 3/7 assay, the proapoptotic properties of both compounds were confirmed. The Annexin V-FITC test revealed that compounds 6 and 8 induce apoptosis in K562 cells. Both compounds inhibit the release of proinflammatory interleukin 6 (IL-6) in K562 cells. Additionally, all compounds were screened for their antibacterial activities using standard and clinical strains. Within the studied group, compound 7 showed moderate activity towards Gram-positive strains in antimicrobial studies, with MIC values ranging from 16 to 64 µg/mL.

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JMJD3-regulated expression of IL-6 is involved in the proliferation and chemosensitivity of acute myeloid leukemia cells

Cited by 8 publications

References 42 publications

The Cross Marks the Spot: The Emerging Role of JmjC Domain-Containing Proteins in Myeloid Malignancies

The Cross Marks the Spot: The Emerging Role of JmjC Domain-Containing Proteins in Myeloid Malignancies

Quantitative phosphoproteomic analysis reveals chemoresistance-related proteins and signaling pathways induced by rhIL-6 in human osteosarcoma cells

New Derivatives of 1-(3-Methyl-1-Benzofuran-2-yl)Ethan-1-one: Synthesis and Preliminary Studies of Biological Activity

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