Comprehensive Map of the Regulated Cell Death Signaling Network: A Powerful Analytical Tool for Studying Diseases

The processes leading to, or avoiding cell death are widely studied, because of their frequent perturbation in various diseases. Cell death occurs in three highly interconnected steps: Initiation, signaling and execution. We used a systems biology approach to gather information about all known modes of regulated cell death (RCD). Based on the experimental data retrieved from literature by manual curation, we graphically depicted the biological processes involved in RCD in the form of a seamless comprehensive signaling network map. The molecular mechanisms of each RCD mode are represented in detail. The RCD network map is divided into 26 functional modules that can be visualized contextually in the whole seamless network, as well as in individual diagrams. The resource is freely available and accessible via several web platforms for map navigation, data integration, and analysis. The RCD network map was employed for interpreting the functional differences in cell death regulation between Alzheimer’s disease and non-small cell lung cancer based on gene expression data that allowed emphasizing the molecular mechanisms underlying the inverse comorbidity between the two pathologies. In addition, the map was used for the analysis of genomic and transcriptomic data from ovarian cancer patients that provided RCD map-based signatures of four distinct tumor subtypes and highlighted the difference in regulations of cell death molecular mechanisms.

[1]  Andres Metspalu,et al.  Gene Expression Profiles of Non-Small Cell Lung Cancer: Survival Prediction and New Biomarkers , 2011, Oncology.

[2]  Samik Ghosh,et al.  AlzPathway: a comprehensive map of signaling pathways of Alzheimer’s disease , 2012, BMC Systems Biology.

[3]  S. Lipton,et al.  Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018 , 2018, Cell Death & Differentiation.

[4]  C. Gilks,et al.  Ovarian carcinoma pathology and genetics: recent advances. , 2009, Human pathology.

[5]  P E Bourne,et al.  The apoptosis database , 2003, Cell Death and Differentiation.

[6]  R. Hoffmann.  A wiki for the life sciences where authorship matters , 2008, Nature Genetics.

[7]  B. Hyman,et al.  Neuronal NLRP1 inflammasome activation of Caspase-1 coordinately regulates inflammatory interleukin-1-beta production and axonal degeneration-associated Caspase-6 activation , 2015, Cell Death and Differentiation.

[8]  Dhruv Chauhan,et al.  A Genome-wide CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) Screen Identifies NEK7 as an Essential Component of NLRP3 Inflammasome Activation* , 2015, The Journal of Biological Chemistry.

[9]  Zhongqiu Lin,et al.  Expression and prognostic value of WISP‐1 in patients with endometrial endometrioid adenocarcinoma , 2011, The journal of obstetrics and gynaecology research.

[10]  Kun-Liang Guan,et al.  Autophagy regulation by nutrient signaling , 2013, Cell Research.

[11]  D. Vučić,et al.  Diverse ubiquitin linkages regulate RIP kinases-mediated inflammatory and cell death signaling , 2017, Cell Death and Differentiation.

[12]  Emmanuel Barillot,et al.  BiNoM 2.0, a Cytoscape plugin for accessing and analyzing pathways using standard systems biology formats , 2013, BMC Systems Biology.

[13]  T. Dawson,et al.  Parthanatos, a messenger of death. , 2009, Frontiers in bioscience.

[14]  Yukiko Matsuoka,et al.  Using process diagrams for the graphical representation of biological networks , 2005, Nature Biotechnology.

[15]  E. Barillot,et al.  ROMA: Representation and Quantification of Module Activity from Target Expression Data , 2016, Front. Genet..

[16]  Peter E. Czabotar,et al.  Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy , 2013, Nature Reviews Molecular Cell Biology.

[17]  Chulhee Choi,et al.  Caspase-dependent generation of reactive oxygen species in human astrocytoma cells contributes to resistance to TRAIL-mediated apoptosis , 2010, Cell Death and Differentiation.

[18]  Tzeng-Ji Chen,et al.  Does Alzheimer’s Disease Protect against Cancers? A Nationwide Population-Based Study , 2012, Neuroepidemiology.

[19]  Benjamin J. Raphael,et al.  Integrated Genomic Analyses of Ovarian Carcinoma , 2011, Nature.

[20]  Inder M. Verma,et al.  NF-κB, an Active Player in Human Cancers , 2014, Cancer Immunology Research.

[21]  H. Horvitz,et al.  Mechanisms and functions of cell death. , 1991, Annual review of cell biology.

[22]  E. Barillot,et al.  A comprehensive modular map of molecular interactions in RB/E2F pathway , 2008, Molecular systems biology.

[23]  Henning Hermjakob,et al.  The Reactome pathway Knowledgebase , 2015, Nucleic acids research.

[24]  P. Csermely,et al.  Autophagy Regulatory Network — A systems-level bioinformatics resource for studying the mechanism and regulation of autophagy , 2015, Autophagy.

[25]  Lorenzo Galluzzi,et al.  Mitochondrial Control of Cellular Life, Stress, and Death , 2012, Circulation research.

[26]  So-Ra Lee,et al.  Post-translational modification of the death receptor complex as a potential therapeutic target in cancer , 2019, Archives of Pharmacal Research.

[27]  Bernd Thiede,et al.  ApoptoProteomics, an Integrated Database for Analysis of Proteomics Data Obtained from Apoptotic Cells* , 2011, Molecular & Cellular Proteomics.

[28]  Wenqing Gao,et al.  Pyroptosis: Gasdermin-Mediated Programmed Necrotic Cell Death. , 2017, Trends in biochemical sciences.

[29]  E. Goode,et al.  Prognostic and therapeutic relevance of molecular subtypes in high-grade serous ovarian cancer. , 2014, Journal of the National Cancer Institute.

[30]  G. Kroemer,et al.  The protein disulfide isomerases PDIA4 and PDIA6 mediate resistance to cisplatin-induced cell death in lung adenocarcinoma , 2014, Cell Death and Differentiation.

[31]  H. Kitano,et al.  A comprehensive map of the mTOR signaling network , 2010, Molecular systems biology.

[32]  Junfeng Xia,et al.  Identification of ovarian cancer subtype-specific network modules and candidate drivers through an integrative genomics approach , 2015, Oncotarget.

[33]  Francesca Pentimalli,et al.  Cell death pathologies: targeting death pathways and the immune system for cancer therapy , 2018, Genes & Immunity.

[34]  Seth L Masters,et al.  Inflammasome Priming in Sterile Inflammatory Disease. , 2017, Trends in molecular medicine.

[35]  Richard Mohs,et al.  Caspase gene expression in the brain as a function of the clinical progression of Alzheimer disease. , 2003, Archives of neurology.

[36]  Inna Kuperstein,et al.  Signalling maps in cancer research: construction and data analysis , 2018, Database J. Biol. Databases Curation.

[37]  T Avril,et al.  Endoplasmic reticulum stress signaling and chemotherapy resistance in solid cancers , 2017, Oncogenesis.

[38]  T. Dawson,et al.  Parthanatos: mitochondrial‐linked mechanisms and therapeutic opportunities , 2014, British journal of pharmacology.

[39]  Yuji Kajiwara,et al.  The human-specific CASP4 gene product contributes to Alzheimer-related synaptic and behavioural deficits. , 2016, Human molecular genetics.

[40]  Henning Hermjakob,et al.  The Reactome pathway knowledgebase , 2013, Nucleic Acids Res..

[41]  Alexei Degterev,et al.  Identification of a Molecular Signaling Network that Regulates a Cellular Necrotic Cell Death Pathway , 2008, Cell.

[42]  Kaoru Ogawa,et al.  Autophagy through 4EBP1 and AMPK regulates oxidative stress-induced premature senescence in auditory cells , 2014, Oncotarget.

[43]  Joshy George,et al.  Integrated Genome-Wide DNA Copy Number and Expression Analysis Identifies Distinct Mechanisms of Primary Chemoresistance in Ovarian Carcinomas , 2009, Clinical Cancer Research.

[44]  Minoru Kanehisa,et al.  The KEGG database. , 2002, Novartis Foundation symposium.

[45]  K. Tomczak,et al.  The Cancer Genome Atlas (TCGA): an immeasurable source of knowledge , 2015, Contemporary oncology.

[46]  Alfonso Valencia,et al.  A molecular hypothesis to explain direct and inverse co-morbidities between Alzheimer’s Disease, Glioblastoma and Lung cancer , 2017, Scientific Reports.

[47]  V. Dixit,et al.  Death receptors: signaling and modulation. , 1998, Science.

[48]  Winnie S. Liang,et al.  Alzheimer's disease is associated with reduced expression of energy metabolism genes in posterior cingulate neurons , 2008, Proceedings of the National Academy of Sciences.

[49]  Matthew L. Albert,et al.  Dying cells actively regulate adaptive immune responses , 2017, Nature Reviews Immunology.

[50]  E. Barillot,et al.  Atlas of Cancer Signalling Network: a systems biology resource for integrative analysis of cancer data with Google Maps , 2015, Oncogenesis.

[51]  Heikki Tanila,et al.  Expression of interleukin-18 is increased in the brains of Alzheimer's disease patients , 2009, Neurobiology of Aging.

[52]  Junying Yuan,et al.  Regulation of RIPK1 activation by TAK1-mediated phosphorylation dictates apoptosis and necroptosis , 2017, Nature Communications.

[53]  Sarala M. Wimalaratne,et al.  The Systems Biology Graphical Notation , 2009, Nature Biotechnology.

[54]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[55]  Livia Perfetto,et al.  SIGNOR: a database of causal relationships between biological entities , 2015, Nucleic Acids Res..

[56]  Zhi-Yong Wu,et al.  YWHAZ promotes ovarian cancer metastasis by modulating glycolysis. , 2018, Oncology reports.

[57]  P. Vandenabeele,et al.  Molecular mechanisms of necroptosis: an ordered cellular explosion , 2010, Nature Reviews Molecular Cell Biology.

[58]  Xiaohua Wu,et al.  N-myc downstream regulated gene 1 acts as a tumor suppressor in ovarian cancer. , 2014, Oncology reports.

[59]  Roman Jaksik,et al.  Autophagy, Apoptosis, Mitoptosis and Necrosis: Interdependence Between Those Pathways and Effects on Cancer , 2013, Archivum Immunologiae et Therapiae Experimentalis.

[60]  Feng He,et al.  Systems medicine disease maps: community-driven comprehensive representation of disease mechanisms , 2018, npj Systems Biology and Applications.

[61]  Lorenzo Galluzzi,et al.  Molecular mechanisms of regulated necrosis. , 2014, Seminars in cell & developmental biology.

[62]  S. Dixon,et al.  Emerging roles for lipids in non-apoptotic cell death , 2016, Cell Death and Differentiation.

[63]  J. Silke,et al.  IAP family of cell death and signaling regulators. , 2014, Methods in enzymology.

[64]  Afshin Samali,et al.  New directions in ER stress-induced cell death , 2013, Apoptosis.

[65]  Raffaello Nemni,et al.  The NLRP3 and NLRP1 inflammasomes are activated in Alzheimer’s disease , 2016, Molecular Neurodegeneration.

[66]  G. Latunde-Dada,et al.  Ferroptosis: Role of lipid peroxidation, iron and ferritinophagy. , 2017, Biochimica et biophysica acta. General subjects.

[67]  Peter Vandenabeele,et al.  Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. , 2013, Immunity.

[68]  D. Tang,et al.  Ferroptosis: process and function , 2016, Cell Death and Differentiation.

[69]  Batoul Y. Abdallah,et al.  Heterogeneity of Cell Death , 2013, Cytogenetic and Genome Research.

[70]  Christopher Power,et al.  Inflammasomes in neurological diseases: emerging pathogenic and therapeutic concepts , 2017, Brain : a journal of neurology.

[71]  W. McCluggage,et al.  Morphological subtypes of ovarian carcinoma: a review with emphasis on new developments and pathogenesis. , 2011, Pathology.

[72]  Dexter Pratt,et al.  NDEx 2.0: A Clearinghouse for Research on Cancer Pathways. , 2017, Cancer research.

[73]  M. MacFarlane,et al.  The 'complexities' of life and death: death receptor signalling platforms. , 2012, Experimental cell research.

[74]  Inna Kuperstein,et al.  NaviCell: a web-based environment for navigation, curation and maintenance of large molecular interaction maps , 2013, BMC Systems Biology.

[75]  Antonio Facchiano,et al.  Cancer Microenvironment and Endoplasmic Reticulum Stress Response , 2015, Mediators of inflammation.

[76]  J. Hardy,et al.  Neurobiology of Alzheimer’s Disease: Integrated Molecular, Physiological, Anatomical, Biomarker, and Cognitive Dimensions , 2015, Current Alzheimer research.

[77]  Piotr Gawron,et al.  MINERVA—a platform for visualization and curation of molecular interaction networks , 2016, npj Systems Biology and Applications.

[78]  Carlo Caltagirone,et al.  Inverse occurrence of cancer and Alzheimer disease , 2013, Neurology.

[79]  Chiara Riganti,et al.  PERK induces resistance to cell death elicited by endoplasmic reticulum stress and chemotherapy , 2017, Molecular Cancer.

[80]  Inna Kuperstein,et al.  NaviCom: a web application to create interactive molecular network portraits using multi-level omics data , 2016, bioRxiv.

[81]  Anaïs Baudot,et al.  Editorial: Direct and Inverse Comorbidities Between Complex Disorders , 2016, Front. Physiol..

[82]  Paul G Ekert,et al.  The molecular relationships between apoptosis, autophagy and necroptosis. , 2015, Seminars in cell & developmental biology.

[83]  Samik Ghosh,et al.  A comprehensive map of the influenza A virus replication cycle , 2013, BMC Systems Biology.

[84]  Susumu Goto,et al.  KEGG for integration and interpretation of large-scale molecular data sets , 2011, Nucleic Acids Res..

[85]  Tomio Sasaki,et al.  Altered Expression of Diabetes-Related Genes in Alzheimer's Disease Brains: The Hisayama Study , 2013, Cerebral cortex.

[86]  L. Ouyang,et al.  Programmed cell death pathways in cancer: a review of apoptosis, autophagy and programmed necrosis , 2012, Cell proliferation.

[87]  Denise C. Park,et al.  Toward defining the preclinical stages of Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease , 2011, Alzheimer's & Dementia.

[88]  Kwanjeera Wanichthanarak,et al.  yApoptosis: yeast apoptosis database , 2013, Database J. Biol. Databases Curation.