&lt;p&gt;Tumor necrosis factor &amp;alpha; knockout impaired tumorigenesis in chronic myeloid leukemia cells partly by metabolism modification and miRNA regulation&lt;/p&gt;

Shen, Na; Liu, Songya; Cui, Jieke; Li, Qing; You, Yong; Zhong, Zhaodong; Cheng, Fanjun; Guo, An‐Yuan; Zou, Ping; Yuan, Guolin; Zhu, Xiaojian

doi:10.2147/ott.s197535

Cited by 9 publications

(7 citation statements)

References 34 publications

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“…In fact, TNF has been recognized as a key regulator at all stages of tumor malignancies, including tumorigenesis, cancer cell proliferation, survival, angiogenesis, cellular invasion, and metastasis [33]. Moreover, TNF can stimulate the release of other pro-inflammatory cytokines in larger quantities, thereby perpetuating chronic inflammatory responses [31,38,39]. Building upon this information, our study revealed that K-562 cells release elevated levels of TNF following stimulation by LPS.…”

Section: Discussionsupporting

confidence: 53%

Vitamin C Inhibits Lipopolysaccharide-Induced Hyperinflammatory State of Chronic Myeloid Leukemia Cells through Purinergic Signaling and Autophagy

Pires,

Brandão-Rangel,

Silva-Reis

et al. 2024

Nutrients

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Background: Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the overproduction of white blood cells, leading to symptoms such as fatigue, infections, and other complications. CML patients must take measures to prevent infections to mitigate the exacerbation of cancer cell proliferation and comorbidities. Methods: This study investigated whether vitamin C can suppress the hyperinflammatory activation of K-562 cells induced by lipopolysaccharide (LPS) and whether purinergic signaling (ATP and P2X7 receptor) and autophagy play a role in it. Two different doses of vitamin C (5 µg/mL and 10 µg/mL) were employed, along with the lysosome inhibitor chloroquine (CQ; 100 µM), administered 2 h prior to LPS stimulation (10 ng/mL) for a duration of 22 h in K-562 cells (3 × 105 cells/mL/well). Results: Both doses of vitamin C reduced the release of interleukin-6 (IL-6) (5 µg/mL, p < 0.01 and 10 µg/mL, p < 0.01) and tumor necrosis factor (TNF) (5 µg/mL, p < 0.01 and 10 µg/mL, p < 0.01) induced by LPS. Furthermore, in LPS + CQ-stimulated cells, vitamin C at a concentration of 10 µg/mL inhibited the expression of LC3-II (p < 0.05). Conversely, both doses of vitamin C led to the release of the anti-inflammatory cytokine interleukin-10 (IL-10) (5 µg/mL, p < 0.01 and 10 µg/mL, p < 0.01), while only the 10 µg/mL dose of vitamin C induced the release of Klotho (10 µg/mL, p < 0.01). In addition, both doses of vitamin C reduced the accumulation of ATP (5 µg/mL, p < 0.01 and 10 µg/mL, p < 0.01) and decreased the expression of the P2X7 receptor at the mRNA level. Conclusions: Vitamin C inhibits the hyperinflammatory state induced by LPS in K-562 cells, primarily by inhibiting the ATP accumulation, P2X7 receptor expression, and autophagy signaling.

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Section: Discussionsupporting

confidence: 53%

Vitamin C Inhibits Lipopolysaccharide-Induced Hyperinflammatory State of Chronic Myeloid Leukemia Cells through Purinergic Signaling and Autophagy

Pires,

Brandão-Rangel,

Silva-Reis

et al. 2024

Nutrients

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“…TNFα and IL-6 have been shown to support stem and progenitor cell survival and proliferation in CML [50][51][52][53]. Additionally, several groups have reported a role for cytokines in the CML bone marrow microenvironment [53][54][55][56][57], and blockade of extrinsic survival signals was shown to restore sensitivity of CML cells to TKIs [58,59]. Since our RNA-seq data implicated TNFα signaling via NF-κB, we hypothesized that autocrine TNFα production was responsible for further NF-κB activation in TKI resistance.…”

Section: Knockdown Of Psmd1 or Psmd3 Reduced Nf-κb Protein Expressionmentioning

confidence: 78%

Proteasome 26S subunit, non-ATPases 1 (PSMD1) and 3 (PSMD3), play an oncogenic role in chronic myeloid leukemia by stabilizing nuclear factor-kappa B

et al. 2021

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Tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 have revolutionized therapy for chronic myeloid leukemia (CML), paving the way for clinical development in other diseases. Despite success, targeting leukemic stem cells and overcoming drug resistance remain challenges for curative cancer therapy. To identify drivers of kinase-independent TKI resistance in CML, we performed genome-wide expression analyses on TKI-resistant versus sensitive CML cell lines, revealing a nuclear factor-kappa B (NF-κB) expression signature. Nucleocytoplasmic fractionation and luciferase reporter assays confirmed increased NF-κB activity in the nucleus of TKI-resistant versus sensitive CML cell lines and CD34+ patient samples. Two genes that were upregulated in TKI-resistant CML cells were proteasome 26S subunit, non-ATPases 1 (PSMD1) and 3 (PSMD3), both members of the 19S regulatory complex in the 26S proteasome. PSMD1 and PSMD3 were also identified as survival-critical genes in a published small hairpin RNA library screen of TKI resistance. We observed markedly higher levels of PSMD1 and PSMD3 mRNA in CML patients who had progressed to the blast phase compared with the chronic phase of the disease. Knockdown of PSMD1 or PSMD3 protein correlated with reduced survival and increased apoptosis in CML cells, but not in normal cord blood CD34+ progenitors. Luciferase reporter assays and immunoblot analyses demonstrated that PSMD1 and PSMD3 promote NF-κB protein expression in CML, and that signal transducer and activator of transcription 3 (STAT3) further activates NF-κB in scenarios of TKI resistance. Our data identify NF-κB as a transcriptional driver in TKI resistance, and implicate PSMD1 and PSMD3 as plausible therapeutic targets worthy of future investigation in CML and possibly other malignancies.

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“…In addition, this targeting approach for oncogenic fusion genes has been successfully used to impair the BCR-ABL1 fusion protein expression in chronic myeloid leukemia K562 cell line, in vitro and on in vivo xenograft athymic nude mice models [ 67 ]. With this cell model, others have shown that tumor necrosis factor-alpha ( TNF-α ) gene knockout can markedly reduce the proliferation and clonogenic potential of K562 cells in vitro, and the edited cells displayed impaired tumor xenograft growth in mice models [ 68 ]. Furthermore, altered TNF-α function as a result of gene editing was associated with a deregulated metabolism profile.…”

Section: Approaches For Therapeutic Genome Editing In Human Malignant...mentioning

confidence: 99%

“…Furthermore, altered TNF-α function as a result of gene editing was associated with a deregulated metabolism profile. The expression profile of TNF-α knockout cells revelated differentially expressed miRNAs involved in the cell cycle, apoptosis, and other pathways associated with the malignant phenotype [ 68 ]. Altered metabolism in malignant cells is not something new, and a positive correlation between increased lipid metabolism and cancer development and progression has been established (reviewed in [ 69 , 70 ]).…”

Section: Approaches For Therapeutic Genome Editing In Human Malignant...mentioning

confidence: 99%

Genome Editing Approaches with CRISPR/Cas9 for Cancer Treatment: Critical Appraisal of Preclinical and Clinical Utility, Challenges, and Future Research

Chira

Nuțu

Isacescu

et al. 2022

Cells

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The increasing burden on human malignant diseases became a major concern for healthcare practitioners, that must deal with tumor relapse and the inability to efficiently treat metastasis, in addition to side effects. Throughout the decades, many therapeutic strategies have been employed to improve the clinical outcomes of cancer patients and great efforts have been made to develop more efficient and targeted medicines. The malignant cell is characterized by genetic and epigenetic modifications, therefore targeting those specific drivers of carcinogenesis is highly desirable. Among the genome editing technologies, CRISPR/Cas9 stood as a promising candidate for cancer treatment alternatives, due to its low complexity design. First described as a defense mechanism of bacteria against invading foreign DNA, later it was shown that CRISPR components can be engineered to target specific DNA sequences in a test tube, a discovery that was awarded later with the Nobel Prize in chemistry for its rapid expansion as a reliable genome editing tool in many fields of research, including medicine. The present paper aims of describing CRISPR/Cas9 potential targets for malignant disorders, and the approaches used for achieving this goal. Aside from preclinical studies, we also present the clinical trials that use CRISPR-based technology for therapeutic purposes of cancer. Finally, a summary of the presented studies adds a more focused view of the therapeutic value CRISPR/Cas9 holds and the associated shortcomings.

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<p>Tumor necrosis factor α knockout impaired tumorigenesis in chronic myeloid leukemia cells partly by metabolism modification and miRNA regulation</p>

Cited by 9 publications

References 34 publications

Vitamin C Inhibits Lipopolysaccharide-Induced Hyperinflammatory State of Chronic Myeloid Leukemia Cells through Purinergic Signaling and Autophagy

Vitamin C Inhibits Lipopolysaccharide-Induced Hyperinflammatory State of Chronic Myeloid Leukemia Cells through Purinergic Signaling and Autophagy

Proteasome 26S subunit, non-ATPases 1 (PSMD1) and 3 (PSMD3), play an oncogenic role in chronic myeloid leukemia by stabilizing nuclear factor-kappa B

Genome Editing Approaches with CRISPR/Cas9 for Cancer Treatment: Critical Appraisal of Preclinical and Clinical Utility, Challenges, and Future Research

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