Necroptosis throws novel insights on patient classification and treatment strategies for hepatocellular carcinoma

Hu, Bowen; Gao, Jie; Shi, Jihua; Zhang, Feng; Shi, Chengcheng; Wang, Zhihui; Guo, Wenzhi; Zhang, Shuijun

doi:10.3389/fimmu.2022.970117

Cited by 5 publications

(5 citation statements)

References 47 publications

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“…Necroptosis, another important mechanism of PCD also causes cell membrane rupture, cell swelling, and lysis. The molecular mechanisms underlying necroptosis are reported to depend critically on receptor-interacting serine-threonine kinase 1 (RIPK1), RIPK3, and MLKL, regardless of the upstream trigger [47]. Que induced cell death through pyroptosis, not through necroptosis activation, based on the following evidence: first, the RIPK3 inhibitor GSK'872 accelerated cell death triggered by Que in colon cancer cells, instead of neutralizing the cytotoxicity effect; second, Que inhibited the activation of the RIPK3-MLKL axis; moreover, the protein expression level related to the NLRP3 inflammasome-GSDMD signaling pathway had increased, which was attributed to pyroptosis induction, and the shRNA of the NLRP3 inflammasome-GSDMD signaling pathway markedly rescued Que-induced cell death.…”

Section: Discussionmentioning

confidence: 99%

Quercetin-induced pyroptosis in colon cancer through NEK7-mediated NLRP3 inflammasome-GSDMD signaling pathway activation

Feng

2024

Am J Cancer Res

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Pyroptosis, a gasdermin-mediated lytic cell death, is a new hotspot topic in cancer research, and induction of tumor pyroptosis has emerged as a new target in cancer management. Quercetin (Que), a natural substance, demonstrates promising anticancer action. However, further information is required to fully comprehend the function and mechanism of Que in pyroptosis in colon cancer. This study revealed the underlying mechanism of Queinduced pyroptosis in colon cancer in vitro and in vivo. Que inhibited colon cancer cell growth through gasdermin D (GSDMD)-mediated pyroptosis. Depletion of GSDMD, rather than gasdermin E (GSDME), reversed the cytotoxic effects of Que on colon cancer cells. Que treatment upregulated NIMA-related kinase 7 (NEK7) protein expression, thus facilitating the assembly of the NLRP3 inflammasome and cleavage of GSDMD. NEK7 silencing resulted in colon cancer cell growth in vitro and in vivo. Mechanistically, NEK7 depression restrained the activation of the NLRP3 inflammasome-GSDMD pathway, thus attenuating pyroptosis triggered by Que in colon cancer cells. Furthermore, lower NEK7 and NLRP3 expression levels indicated colon cancer progression. Our results unveiled a novel pattern of anti-colon cancer activity of Que, and activation of NEK7-mediated pyroptosis is potentially a promising therapeutic target for colon cancer, which provides novel experimental proof for the clinical application of Que.

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Section: Discussionmentioning

confidence: 99%

Quercetin-induced pyroptosis in colon cancer through NEK7-mediated NLRP3 inflammasome-GSDMD signaling pathway activation

Feng

2024

Am J Cancer Res

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“…Before identifying NETlnc, we first screen the intersected lncRNAs in all datasets. Subsequently, we utilized the R package “weighted gene co-expression network analysis (WGCNA)” was utilized to constructed a scale-free gene co-expression network based on previous research ( 25 , 26 ). After ensuring that there were no missing values in the expression matrix data, the samples were clustered, and outlier samples that deviated significantly from the others were removed.…”

Section: Methodsmentioning

confidence: 99%

“…Gene sets of immune checkpoints, extracted from prior research, were used to comprehensively evaluate the immune profile of the tumor microenvironment. Additionally, differences in the Intratumor Heterogeneity, Proliferation, Leukocyte Fraction, and Lymphocyte Infiltration Signature between distinct NETsLnc groups were compared ( 25 ).…”

Section: Methodsmentioning

confidence: 99%

Development of a prognostic Neutrophil Extracellular Traps related lncRNA signature for soft tissue sarcoma using machine learning

Liu,

He,

et al. 2024

Front. Immunol.

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BackgroundSoft tissue sarcoma (STS) is a highly heterogeneous musculoskeletal tumor with a significant impact on human health due to its high incidence and malignancy. Long non-coding RNA (lncRNA) and Neutrophil Extracellular Traps (NETs) have crucial roles in tumors. Herein, we aimed to develop a novel NETsLnc-related signature using machine learning algorithms for clinical decision-making in STS.MethodsWe applied 96 combined frameworks based on 10 different machine learning algorithms to develop a consensus signature for prognosis and therapy response prediction. Clinical characteristics, univariate and multivariate analysis, and receiver operating characteristic curve (ROC) analysis were used to evaluate the predictive performance of our models. Additionally, we explored the biological behavior, genomic patterns, and immune landscape of distinct NETsLnc groups. For patients with different NETsLnc scores, we provided information on immunotherapy responses, chemotherapy, and potential therapeutic agents to enhance the precision medicine of STS. Finally, the gene expression was validated through real-time quantitative PCR (RT-qPCR).ResultsUsing the weighted gene co-expression network analysis (WGCNA) algorithm, we identified NETsLncs. Subsequently, we constructed a prognostic NETsLnc signature with the highest mean c-index by combining machine learning algorithms. The NETsLnc-related features showed excellent and stable performance for survival prediction in STS. Patients in the low NETsLnc group, associated with improved prognosis, exhibited enhanced immune activity, immune infiltration, and tended toward an immunothermal phenotype with a potential immunotherapy response. Conversely, patients with a high NETsLnc score showed more frequent genomic alterations and demonstrated a better response to vincristine treatment. Furthermore, RT-qPCR confirmed abnormal expression of several signature lncRNAs in STS.ConclusionIn conclusion, the NETsLnc signature shows promise as a powerful approach for predicting the prognosis of STS. which not only deepens our understanding of STS but also opens avenues for more targeted and effective treatment strategies.

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“…Triggering necrosis in cancer cells is a promising way to avoid the failure of cancer chemotherapy due to apoptosis resistance by bypassing the apoptotic pathway to induce cancer cell death. As such, the molecular mechanisms of necroptosis have been well investigated, which depends critically on receptor-interacting serine-threonine kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like (MLKL), regardless of the upstream trigger ( Hu et al, 2022 ; Yan et al, 2022 ). Currently, only limited experiments have shown the induction of necroptosis in cancer cells by quercetin.…”

Section: Therapeutic Mechanisms Of Quercetin Targeting Non-apoptotic ...mentioning

confidence: 99%

Targeting of non-apoptotic cancer cell death mechanisms by quercetin: Implications in cancer therapy

Yang

Xu²,

Tang³

et al. 2022

Front. Pharmacol.

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The ultimate goal of cancer treatment is to kill cancer cells, based on the use of various therapeutic agents, such as chemotherapy, radiotherapy, or targeted therapy drugs. Most drugs exert their therapeutic effects on cancer by targeting apoptosis. However, alterations in apoptosis-related molecules and thus assisting cells to evade death, eventually lead to tumor cell resistance to therapeutic drugs. The increased incidence of non-apoptotic cell death modes such as induced autophagy, mitotic catastrophe, senescence, and necrosis is beneficial to overcoming multidrug resistance mediated by apoptosis resistance in tumor cells. Therefore, investigating the function and mechanism of drug-induced non-apoptotic cell death modes has positive implications for the development of new anti-cancer drugs and therapeutic strategies. Phytochemicals show strong potential as an alternative or complementary medicine for alleviating various types of cancer. Quercetin is a flavonoid compound widely found in the daily diet that demonstrates a significant role in inhibiting numerous human cancers. In addition to direct pro-tumor cell apoptosis, both in vivo and in vitro experiments have shown that quercetin exerts anti-tumor properties by triggering diverse non-apoptotic cell death modes. This review summarized the current status of research on the molecular mechanisms and targets through which quercetin-mediated non-apoptotic mode of cancer cell death, including autophagic cell death, senescence, mitotic catastrophe, ferroptosis, necroptosis, etc.

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Necroptosis throws novel insights on patient classification and treatment strategies for hepatocellular carcinoma

Cited by 5 publications

References 47 publications

Quercetin-induced pyroptosis in colon cancer through NEK7-mediated NLRP3 inflammasome-GSDMD signaling pathway activation

Quercetin-induced pyroptosis in colon cancer through NEK7-mediated NLRP3 inflammasome-GSDMD signaling pathway activation

Development of a prognostic Neutrophil Extracellular Traps related lncRNA signature for soft tissue sarcoma using machine learning

Targeting of non-apoptotic cancer cell death mechanisms by quercetin: Implications in cancer therapy

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