scholarly journals Mechanisms of Deregulation of Apoptosis in Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. SCI-10-SCI-10
Author(s):  
Simone Fulda
Keyword(s):  
Cell Death ◽  
Cancer Therapy ◽  
Programmed Cell Death ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Binding Motif ◽  
Apoptosis Resistance ◽  
Aberrant Expression ◽  
Antiapoptotic Proteins ◽  
Human Cancers

Programmed cell death is a fundamental cellular program that is inherent in every cell of the human body. Apoptosis represents one of the most extensively studied forms of programmed cell death that plays a critical role during various physiological processes as well as in a variety of pathological conditions. Against the background that tissue homeostasis is maintained by a subtle balance between cell death on one side and cell proliferation on the other side, any changes in one of these parameters can form the basis for human diseases. The fact that under normal conditions apoptosis represents a safeguard mechanism to prevent tumorigenesis implies that evasion of apoptosis constitutes a characteristic feature of human cancers. Too little cell death contributes not only to cancer formation, but also to cancer progression and treatment resistance. A better understanding of the mechanisms that are involved in the regulation of apoptosis in human cancers over the last decades has led to the development of novel approaches for exploiting this cellular program for cancer therapy. Also, the elucidation of the molecular mechanisms that underlie the intrinsic apoptosis resistance of human cancers resulted in the identification of target structures that can be exploited for therapeutic purposes. For example, cell death is frequently impaired in cancers by aberrant expression of antiapoptotic proteins, for example "Inhibitor of Apoptosis" (IAP) proteins, which are expressed at high levels in many human cancers. Among the therapeutic approaches that have been developed to target IAP proteins, the most widely used strategy is based on mimicking the IAP-binding motif of second mitochondria-derived activator of caspases (Smac), which functions as an endogenous IAP antagonist. Current and future perspectives on targeting cell death pathways, for example by using Smac mimetics, for therapeutic intervention in human cancers will be discussed. Since antiapoptotic proteins of the BCL-2 family, including BCL-2, BCL-xL and MCL-1, play a critical role in disabling the mitochondrial pathway of apoptosis, these antiapoptotic BCL-2 family proteins have gained a lot of attention for the development of mitochondria-targeted cancer therapeutics. To this end, structure-based, rational drug design has resulted in the development of small-molecule inhibitors of antiapoptotic proteins of the BCL-2 family. The concept to rationally target apoptosis signal transduction pathways has important implications for cancer therapy, since intact apoptosis programs are critical for the therapeutic efficacy of most anticancer therapies. Reactivation of apoptosis not only directly triggers cell death in cancer cells, but also lowers the threshold for apoptosis in response to other apoptotic stimuli, thus sensitizing tumor cells for apoptosis. In principle, the idea to target apoptosis pathways has been translated into first clinical applications. The challenge in future years will be to further exploit this concept for cancer therapy to the best possible extent. Disclosures No relevant conflicts of interest to declare.

scholarly journals Cell Death Pathways as Therapeutic Targets in Rhabdomyosarcoma

Sarcoma ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Simone Fulda
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Acquired Resistance ◽  
Aberrant Expression ◽  
Antiapoptotic Proteins ◽  
Cell Death Pathways ◽  
Rational Development ◽  
Current Therapies ◽  
Key Issues ◽  
Cytotoxic Therapies

Resistance of rhabdomyosarcoma to current therapies remains one of the key issues in pediatric oncology. Since the success of most cytotoxic therapies in the treatment of cancer, for example, chemotherapy, depends on intact signaling pathways that mediate programmed cell death (apoptosis), defects in apoptosis programs in cancer cells may result in resistance. Evasion of apoptosis in rhabdomyosarcoma may be caused by defects in the expression or function of critical mediators of apoptosis or in aberrant expression of antiapoptotic proteins. Therefore, the identification of the molecular mechanisms that confer primary or acquired resistance to apoptosis in rhabdomyosarcoma presents a critical step for the rational development of molecular targeted drugs. This approach will likely open novel perspectives for the treatment of rhabdomyosarcoma.

scholarly journals Mechanisms and Therapeutic Regulation of Pyroptosis in Inflammatory Diseases and Cancer

2020 ◽  
Vol 21 (4) ◽  
pp. 1456 ◽  
Author(s):  
Zhaodi Zheng ◽  
Guorong Li
Keyword(s):  
Cell Death ◽  
Cancer Therapy ◽  
Programmed Cell Death ◽  
Inflammatory Disease ◽  
Therapeutic Target ◽  
Mitochondrial Membrane ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Normal Cells ◽  
Caspase Cleavage

Programmed Cell Death (PCD) is considered to be a pathological form of cell death when mediated by an intracellular program and it balances cell death with survival of normal cells. Pyroptosis, a type of PCD, is induced by the inflammatory caspase cleavage of gasdermin D (GSDMD) and apoptotic caspase cleavage of gasdermin E (GSDME). This review aims to summarize the latest molecular mechanisms about pyroptosis mediated by pore-forming GSDMD and GSDME proteins that permeabilize plasma and mitochondrial membrane activating pyroptosis and apoptosis. We also discuss the potentiality of pyroptosis as a therapeutic target in human diseases. Blockade of pyroptosis by compounds can treat inflammatory disease and pyroptosis activation contributes to cancer therapy.

scholarly journals Comprehensive Analysis of Expression Regulation for RNA m6A Regulators With Clinical Significance in Human Cancers

2021 ◽  
Vol 11 ◽  
Author(s):  
Xiaonan Liu ◽  
Pei Wang ◽  
Xufei Teng ◽  
Zhang Zhang ◽  
Shuhui Song
Keyword(s):  
Dna Methylation ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Critical Role ◽  
Expression Regulation ◽  
The Cancer Genome Atlas ◽  
Aberrant Expression ◽  
Human Cancers ◽  
Cancer Types ◽  
Pan Cancer

BackgroundN6-methyladenosine (m6A), the most abundant chemical modification on eukaryotic messenger RNA (mRNA), is modulated by three class of regulators namely “writers,” “erasers,” and “readers.” Increasing studies have shown that aberrant expression of m6A regulators plays broad roles in tumorigenesis and progression. However, it is largely unknown regarding the expression regulation for RNA m6A regulators in human cancers.ResultsHere we characterized the expression profiles of RNA m6A regulators in 13 cancer types with The Cancer Genome Atlas (TCGA) data. We showed that METTL14, FTO, and ALKBH5 were down-regulated in most cancers, whereas YTHDF1 and IGF2BP3 were up-regulated in 12 cancer types except for thyroid carcinoma (THCA). Survival analysis further revealed that low expression of several m6A regulators displayed longer overall survival times. Then, we analyzed microRNA (miRNA)-regulated and DNA methylation-regulated expression changes of m6A regulators in pan-cancer. In total, we identified 158 miRNAs and 58 DNA methylation probes (DMPs) involved in expression regulation for RNA m6A regulators. Furthermore, we assessed the survival significance of those regulatory pairs. Among them, 10 miRNAs and 7 DMPs may promote cancer initiation and progression; conversely, 3 miRNA/mRNA pairs in kidney renal clear cell carcinoma (KIRC) may exert tumor-suppressor function. These findings are indicative of their potential prognostic values. Finally, we validated two of those miRNA/mRNA pairs (hsa-miR-1307-3p/METTL14 and hsa-miR-204-5p/IGF2BP3) that could serve a critical role for potential clinical application in KIRC patients.ConclusionsOur findings highlighted the importance of upstream regulation (miRNA and DNA methylation) governing m6A regulators’ expression in pan-cancer. As a result, we identified several informative regulatory pairs for prognostic stratification. Thus, our study provides new insights into molecular mechanisms of m6A modification in human cancers.

scholarly journals Clustered γ-Protocadherins Regulate Cortical Interneuron Programmed Cell Death

2020 ◽  
Author(s):  
Walter Mancia ◽  
Julien Spatazza ◽  
Benjamin Rakela ◽  
Ankita Chatterjee ◽  
Viraj Pande ◽  
...  
Keyword(s):  
Cell Death ◽  
Cerebral Cortex ◽  
Programmed Cell Death ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Morphological Properties ◽  
Inhibitory Interneurons ◽  
Wild Type ◽  
Cortical Function ◽  
Brain Functions

AbstractCortical function critically depends on inhibitory/excitatory balance. GABAergic cortical inhibitory interneurons (cINs) are born in the ventral forebrain. After completing their migration into cortex, their final numbers are adjusted-during a period of postnatal development - by programmed cell death (PCD). The mechanisms that regulate cIN elimination remain controversial. Here we show that genes in the protocadherin (Pcdh)-γ gene cluster, but not in the Pcdh-α or Pcdh-β clusters, are required for survival of cINs through a BAX-dependent mechanism. Surprisingly, the physiological and morphological properties of Pcdh-γ deficient and wild type cINs during PCD were indistinguishable. Co-transplantation of wild type and Pcdh-γ deficient interneuron precursor cells demonstrate that: 1) the number of mutant cINs eliminated was much higher than that of wild type cells, but the proportion of mutant or WT cells undergoing cell death was not affected by their density; 2) the presence of mutant cINs increases cell death among wild-type counterparts, and 3) cIN survival is dependent on the expression of Pcdh-γ C3, C4, and C5. We conclude that Pcdh-γ, and specifically γC3, γC4, and γC5, play a critical role in regulating cIN survival during the endogenous period of PCD.SignificanceGABAergic cortical inhibitory interneurons (cINs) in the cerebral cortex originate from the ventral embryonic forebrain. After a long migration, they come together with local excitatory neurons to form cortical circuits. These circuits are responsible for higher brain functions, and the improper balance of excitation/inhibition in the cortex can result in mental diseases. Therefore, an understanding of how the final number of cINs is determined is both biologically and, likely, therapeutically significant. Here we show that cell surface homophilic binding proteins belonging to the clustered protocadherin gene family, specifically three isoforms in the Pcdh-γ cluster, play a key role in the regulation cIN programmed cell death. Co-transplantation of mutant and wild-type cINs shows that Pcdh-γ genes have cell-autonomous and non-cell autonomous roles in the regulation of cIN cell death. This work will help identify the molecular mechanisms and cell-cell interactions that determine how the proper ratio of excitatory to inhibitory neurons is determined in the cerebral cortex.

scholarly journals Aberrant Expression of the Transcription Factors Snail and Slug Alters the Response to Genotoxic Stress

2004 ◽  
Vol 24 (17) ◽  
pp. 7559-7566 ◽  
Author(s):  
Masahiro Kajita ◽  
Karissa N. McClinic ◽  
Paul A. Wade
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Molecular Mechanisms ◽  
Human Cancer ◽  
Genotoxic Stress ◽  
Growth Potential ◽  
Invasive Growth ◽  
Aberrant Expression ◽  
Cell Cell

ABSTRACT Snail and Slug are closely related transcriptional repressors involved in embryonic patterning during metazoan development. In human cancer, aberrant expression of Snail and/or Slug has been correlated with invasive growth potential, a property primarily attributed to their ability to directly repress transcription of genes whose products are involved in cell-cell adhesion, such as E-cadherin, occludin, and claudins. To investigate the molecular mechanisms of alterations in epithelial cell fate mediated by aberrant expression of Snail or Slug, we analyzed the consequences of exogenous expression of these factors in human cancer cells. Aberrant expression of either Snail or Slug led to changes in cell morphology, the loss of normal cell-cell contacts, and the acquisition of invasive growth properties. Snail or Slug expression also promoted resistance to programmed cell death elicited by DNA damage. Detailed molecular analysis revealed direct transcriptional repression of multiple factors with well-documented roles in programmed cell death. Depletion of endogenous Snail by RNA interference led to increased sensitivity to DNA damage accompanied by increased expression of the proapoptotic factors identified as targets of Snail. Thus, aberrant expression of Snail or Slug may promote tumorigenesis through increased resistance to programmed cell death.

scholarly journals Progress in understanding the role of lncRNA in programmed cell death

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Na Jiang ◽  
Xiaoyu Zhang ◽  
Xuejun Gu ◽  
Xiaozhuang Li ◽  
Lei Shang
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Molecular Mechanisms ◽  
Membrane Receptors ◽  
Gene Expressions ◽  
Apoptosis Pathway ◽  
Stem Cell Pluripotency ◽  
Extrinsic Apoptosis ◽  
Related Proteins ◽  
Cycle Regulation

AbstractLong non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides but not translated into proteins. LncRNAs regulate gene expressions at multiple levels, such as chromatin, transcription, and post-transcription. Further, lncRNAs participate in various biological processes such as cell differentiation, cell cycle regulation, and maintenance of stem cell pluripotency. We have previously reported that lncRNAs are closely related to programmed cell death (PCD), which includes apoptosis, autophagy, necroptosis, and ferroptosis. Overexpression of lncRNA can suppress the extrinsic apoptosis pathway by downregulating of membrane receptors and protect tumor cells by inhibiting the expression of necroptosis-related proteins. Some lncRNAs can also act as competitive endogenous RNA to prevent oxidation, thereby inhibiting ferroptosis, while some are known to activate autophagy. The relationship between lncRNA and PCD has promising implications in clinical research, and reports have highlighted this relationship in various cancers such as non-small cell lung cancer and gastric cancer. This review systematically summarizes the advances in the understanding of the molecular mechanisms through which lncRNAs impact PCD.

scholarly journals Molecular basis of disregulation of programmed lymphocytes’ death in chronic viral infection

2006 ◽  
Vol 5 (2) ◽  
pp. 23-34
Author(s):  
V. V. Novitsky ◽  
N. V. Ryazantseva ◽  
O. B. Zhoukova
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Viral Infection ◽  
Immune Cells ◽  
Molecular Basis ◽  
Molecular Mechanisms ◽  
Recent Literature ◽  
Chronic Viral Infection ◽  
Persistent Viruses

The review analyses information from recent literature and results of the authors’ own investigations concerning imbalance of programmed cell death in forming chronic viral infection. Molecular mechanisms of apoptosis modulation of immune cells by persistent viruses are discussed in the article.

scholarly journals Bax Inhibitor 1 (BI-1) as a conservative regulator of Programmed Cell Death

2019 ◽  
Vol 73 ◽  
pp. 681-702
Author(s):  
Mirosław Godlewski ◽  
Agnieszka Kobylińska
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Actin Polymerization ◽  
Functional Condition ◽  
Sphingolipid Metabolism ◽  
Antiapoptotic Proteins ◽  
Crop Tolerance ◽  
Cellular Processes ◽  
C Terminus ◽  
Suicidal Death

Programmed cell death (PCD) is a physiological process in which infected or unnecessary cells due to their suicidal death capability can be selectively eliminated. Pro- and antiapoptotic proteins play an important role in the induction or inhibition of this process. Presented article shows property of Bax-1 (BI-1) inhibitor which is one of the conservative protein associated with the endoplasmic reticulum (ER) as well as its cytoprotective role in the regulation of cellular processes. It was shown that: 1) BI-1 is a small protein consisting of 237 amino acids (human protein - 36 kDa) and has 6 (in animals) and 7 (in plants) α-helical transmembrane domains, 2) BI-1 is expressed in all organisms and in most tissues, moreover its level depends on the functional condition of cells and it is involved in the development or reaction to biotic and abiotic stresses, 3) BI-1 forms a pH-dependent Ca2+ channel enabling release of these ions from the ER, 4) cytoprotective effects of BI-1 requires a whole, unchanged C-terminus, 5) BI-1 can interact directly with numerous other proteins, BI-1 protein affects numerous cellular processes, including: counteracting ER stress, oxidative stress, loss of cellular Ca2+ homeostasis as well as this protein influences on sphingolipid metabolism, autophagy, actin polymerization, lysosomal activity and cell proliferation. Studies of BI-1 functions will allow understanding the mechanisms of anticancer therapy or increases the knowledge of crop tolerance to environmental stresses.

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