Caspase-Independent Regulated Necrosis Pathways as Potential Targets in Cancer Management

Lou, Jianyao; Zhou, Yunxiang; Feng, Zengyu; Ma, Mindi; Yao, Yanlai; Wang, Yali; Deng, Yongchuan; Wu, Yulian

doi:10.3389/fonc.2020.616952

Cited by 24 publications

(20 citation statements)

References 257 publications

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“…However, the necroptosis pathway may be a double-edged sword for cancer therapy. Necroptotic cells are characterized by the rupture of the cell membrane and the release of cell contents, resulting in a proinflammatory response, which might facilitate tumor progression via promoting of tumor cell growth and survival, angiogenesis, invasion, and metastasis …”

Section: Necroptosis and Relevant Small Molecules In Cancermentioning

confidence: 99%

Targeting Regulated Cell Death with Pharmacological Small Molecules: An Update on Autophagy-Dependent Cell Death, Ferroptosis, and Necroptosis in Cancer

Xie

et al. 2022

J. Med. Chem.

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Regulated cell death is a widely attractive subject among the topics of cancer therapy and has gained some advances for discovery of targeted anticancer drugs. In the past decade, nonapoptotic regulated cell death has been implicated in the development and therapeutic responses of a variety of human cancers. Hitherto, targeting autophagy-dependent cell death (ADCD), ferroptosis, and necroptosis with small molecules has been emerging as a hopeful strategy for the improvement of potential cancer therapy, which may have an advantage to bypass the apoptosis-resistance machinery. Thus, in this perspective, we concentrate on the key molecular insights into ADCD, ferroptosis, and necroptosis and summarize the corresponding small molecules in potential cancer therapy. Moreover, the relationships between the three subroutines and small molecules modulating the crosstalk are discussed. We believe that these inspiring findings would be advantageous to exploiting more potential targets and pharmacological small molecules in future cancer treatment.

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Section: Necroptosis and Relevant Small Molecules In Cancermentioning

confidence: 99%

Targeting Regulated Cell Death with Pharmacological Small Molecules: An Update on Autophagy-Dependent Cell Death, Ferroptosis, and Necroptosis in Cancer

Xie

et al. 2022

J. Med. Chem.

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“…Twenty-ve necroptosis-related genes were extracted from the MSigDB team (GOBP_NECROPTOTIC_SIGNALING_PATHWAY) and previous reviews, which are presented in the Additional le 5: Table S1 [13][14][15][16][17]. SNV and CNV analyses were performed utilizing the "maftools" package and the "Rcircos" packages, respectively [18,19].…”

Section: Investigation Of the Expressions Of Necroptosis-related Genesmentioning

confidence: 99%

A Necroptosis-Related Gene Signature for Predicting Prognosis, Immune Landscape, and Therapy Sensitivity in Hepatocellular Carcinoma

Chen

Wang

Zhou

et al. 2022

Preprint

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Background: Hepatocellular carcinoma (HCC) remains a growing threat to global health. Necroptosis is a newly discovered regulated cell necrosis that plays a vital role in cancer development. Thus, we conducted this study to develop a predictive signature based on necroptosis-related genes.Methods: The tumor samples in The Cancer Genome Atlas (TCGA) Liver Hepatocellular Carcinoma (LIHC) cohort were subtyped using the consensus clustering algorithm. Univariate Cox regression and LASSO-Cox analysis were performed to construct a gene signature model from differentially expressed genes between tumor clusters. Then we integrated TNM stage and the prognostic model to build a nomogram. The gene signature and the nomogram were externally validated in the GSE14520 cohort from the gene expression omnibus (GEO) and LIRP-JP cohort from the International Cancer Genome Consortium (ICGC). Predictive performance evaluation was conducted using Kaplan-Meier plot, time-dependent receiver operating characteristic curve, principal components analysis, concordance index, and decision curve analysis. The tumor microenvironment was estimated using seven published methods. Finally, we also predicted the drug responses to immunotherapy, conventional chemotherapy and molecular-targeted therapy using two algorithms and two datasets. Results: We identified two necroptosis-related clusters and a ten-gene signature (MTMR2, CDCA8, S100A9, ANXA10, G6PD, SLC1A5, SLC2A1, SPP1, PLOD2, and MMP1). The gene signature and the nomogram had good predictive ability in TCGA, ICGC, and GEO cohorts. The risk score was positively associated with the degree of necroptosis and immune infiltration (especially immunosuppressive cells). The high-risk group could benefit more from immunotherapy. Chemotherapy and molecular-targeted therapy should be adapted to the molecular profiles of each patient.Conclusion: The necroptosis-related gene signature provides reliable evidence for prognosis prediction, comprehensive treatment, and new therapeutic targets for HCC patients. The nomogram can further improve predictive accuracy.

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“…KRAS is one of the main driving genes in pancreatic cancer. More than 90% of patients with pancreatic cancer have KRAS carcinogenic point mutations, which result in the constitutive activation of the RAS signaling pathway [12][13][14]. RAS signal transduction regulates multiple cellular biological processes in pancreatic ductal adenocarcinoma, including cell proliferation, migration, metabolism, and autophagy [15].…”

Section: Abnormal Kras Activation Induces Itga2 Overexpression In Pan...mentioning

confidence: 99%

Overexpressed Integrin Alpha 2 Inhibits the Activation of the Transforming Growth Factor β Pathway in Pancreatic Cancer via the TFCP2-SMAD2 Axis

Cai

Gao

Wen

et al. 2021

Preprint

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BackgroundIntegrin alpha 2 (ITGA2) has been recently reported to be an oncogene and to play crucial roles in tumor cell proliferation, invasion, metastasis, and angiogenesis. Our previous study showed that ITGA2 was overexpressed in pancreatic cancer and promoted its progression. However, the mechanism of ITGA2 overexpression and other mechanisms for promoting the progression of pancreatic cancer are still unclear. MethodsThe GEPIA database was used to confirm the expression of ITGA2 in pancreatic cancer. To verify the influence of ITGA2 and TGF-β on the morphological changes of pancreatic cancer and tumor cell progression, we conduct CCK8 test, plate cloning, flow cytometry experiments and animal experiments. Then we conduct Western blot, RT-qPCR to explore the relationship between ITGA2 and TGF-β, and then find the key molecules which can regulate them by immunoprecipitation, Western blot, RT-qPCR, CHIP, nuclear and cytoplasmic separation test.ResultsThe results of the present study show that the abnormal activation of KRAS induced the overexpression of ITGA2 in pancreatic cancer. Moreover, ITGA2 expression significantly suppressed the activation of the TGF-β pathway. ITGA2 silencing enhanced the anti-pancreatic cancer proliferation and tumor growth effects of TGF-β. Mechanistically, ITGA2 expression suppressed the activation of the TGF-β pathway by inhibiting the SMAD2 expression transcriptionally. In addition, it interacted with and inhibited the nuclear translocation of TFCP2, which induced the SMAD2 expression as a transcription factor. Furthermore, TFCP2 also induced ITGA2 expression as a transcription factor, and the TFCP2 feedback regulated the ITGA2-TFCP2-SMAD2 pathway. ConclusionTaken together, our results indicate that ITGA2 expression inhibited the activation of the TGF-β pathway in pancreatic cancer via the TFCP2-SMAD2 axis. Therefore, especially when combined with TGF-β treatment, ITGA2 might be a potential clinical therapeutic target for pancreatic cancer.

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Caspase-Independent Regulated Necrosis Pathways as Potential Targets in Cancer Management

Cited by 24 publications

References 257 publications

Targeting Regulated Cell Death with Pharmacological Small Molecules: An Update on Autophagy-Dependent Cell Death, Ferroptosis, and Necroptosis in Cancer

Targeting Regulated Cell Death with Pharmacological Small Molecules: An Update on Autophagy-Dependent Cell Death, Ferroptosis, and Necroptosis in Cancer

A Necroptosis-Related Gene Signature for Predicting Prognosis, Immune Landscape, and Therapy Sensitivity in Hepatocellular Carcinoma

Overexpressed Integrin Alpha 2 Inhibits the Activation of the Transforming Growth Factor β Pathway in Pancreatic Cancer via the TFCP2-SMAD2 Axis

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