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Apoptosis signaling pathways. Abbreviations: TRADD, TNF receptor-associated death domain protein; FADD, Fas-associated death domain protein; Bid, BH3 interacting-domain death agonist; Bak, Bcl-2 homologous antagonist/killer; tBid, truncated BID; Bax, Bcl-2 associated X protein; APAF-1, apoptotic protease activating factor-1; Bcl-2, B-cell lymphoma 2, Bcl-xL; B-cell lymphoma-extra large.
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The pathogenesis of many diseases is most closely related to inappropriate apoptosis (either too little or too much) and cancer is one of the situations where too little apoptosis happens, leading to malignant cells that highly proliferate. Defects at any points along apoptotic pathways may lead to malignant transformation of the affected cells, tu...
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Context 1
... released cytochrome c binds to APAF-1 to facilitate the formation of the apoptosome, a wheel shaped heptametrical complex, which can then recruit and activate pro-caspase-9. Consequently, caspase-9 activates effector caspases (caspase-3/-7) that eventually lead to apoptosis (Figure 1) [39][40][41]. ...
Context 2
... of death receptors with death ligands causes conformational change in death domain and consequently recruits apoptosis-related adaptor proteins that associate with procaspase-8/-10. At this point, a death-inducing signaling complex (DISC) consisting of the death receptor, an adaptor molecule, and pro-caspase-8/−10 is formed, resulting in the auto-catalytic activation of procaspases (Figure 1). The activated form of the caspase-8/-10 enzyme, as an initiator caspase, subsequently cleaves and activates other downstream or executioner caspases [42,43]. ...
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Citations
... Furthermore, dying cells can release pro-survival factors, intensifying paracrine signaling and facilitating repopulation [183,184]. As the original concept that cancer cells are passive subjects of natural selection evolves, enhancing apoptosis emerges as a turning point and a double-edged sword in cancer therapy [185]. To date, three mechanisms of tumor reprogramming in response to the initiation of apoptosis have been proposed: apoptosis-induced proliferation, apoptosis-induced nuclear expulsion, and anastasis ( Fig. 3) [29]. ...
Clear cell renal cell carcinoma (ccRCC) is the most prevalent subtype of renal cancer, accounting for approximately 80% of all renal cell cancers. Due to its exceptional inter-and intratumor heterogeneity, it is highly resistant to conventional systemic therapies. Targeting the evasion of cell death, one of cancer's hallmarks, is currently emerging as an alternative strategy for ccRCC. In this article, we review the current state of apoptosis-inducing therapies against ccRCC, including antisense oligonucleotides, BH3 mimetics, histone deacetylase in-hibitors, cyclin-kinase inhibitors, inhibitors of apoptosis protein antagonists, and monoclonal antibodies. Although preclinical studies have shown encouraging results, these compounds fail to improve patients' outcomes significantly. Current evidence suggests that inducing apoptosis in ccRCC may promote tumor progression through apoptosis-induced proliferation, anastasis, and apoptosis-induced nuclear expulsion. Therefore, re-evaluating this approach is expected to enable successful preclinical-to-clinical translation.
... Conversely, their decreased expression in cancer cells might lead to apoptosis evasion [15][16][17][18]. Dysregulation between pro-apoptotic and anti-apoptotic proteins is a fundamental element in tumorigenesis, and therefore, any distortions in the expression of RTN4/Nogo, as pro-apoptotic proteins, may increase the susceptibility to cancer, including BC [75,76]. Several mechanisms for the pro-apoptotic activity of Nogo isoforms have been so far described: inducing ER stress and signaling pathways, expressing survivin, interacting with anti-apoptotic proteins such as the Bcl-xL-Bcl-2 family and c-FLIP, and interacting with the JNK-c-Jun MAPK signaling pathways [15][16][17][18]51]. ...
Breast cancer (BC) is a complex disease caused by molecular events that disrupt cellular survival and death. Discovering novel biomarkers is still required to better understand and treat BC. The reticulon-4 (RTN4) gene, encoding Nogo proteins, plays a critical role in apoptosis and cancer development, with genetic variations affecting its function. We investigated the rs34917480 in RTN4 and its association with BC risk in an Iranian population sample. We also predicted the rs34917480 effect on RTN4 mRNA structure and explored the RTN4’s protein–protein interaction network (PPIN) and related pathways. In this case–control study, 437 women (212 BC and 225 healthy) were recruited. The rs34917480 was genotyped using AS-PCR, mRNA secondary structure was predicted with RNAfold, and PPIN was constructed using the STRING database. Our findings revealed that this variant was associated with a decreased risk of BC in heterozygous (p = 0.012), dominant (p = 0.015), over-dominant (p = 0.017), and allelic (p = 0.035) models. Our prediction model showed that this variant could modify RTN4’s mRNA thermodynamics and potentially its translation. RTN4’s PPIN also revealed a strong association with apoptosis regulation and key signaling pathways highly implicated in BC. Consequently, our findings, for the first time, demonstrate that rs34917480 could be a protective factor against BC in our cohort, probably via preceding mechanisms.
... Since it has been established that apoptosis plays an important role in the pathogenesis of many diseases, including cancer, an understanding of its mechanism is vital. One condition where too little apoptosis takes place is cancer, which results in malignant cells that are resistant to induction of cell death [56,57]. There are a number of pathways that are involved in apoptosis, including extrinsic and intrinsic pathways, which can be compromised at any point along the way, resulting in malignant transformation and metastasis of tumour cells and resistance to anticancer therapy [56,57]. ...
... One condition where too little apoptosis takes place is cancer, which results in malignant cells that are resistant to induction of cell death [56,57]. There are a number of pathways that are involved in apoptosis, including extrinsic and intrinsic pathways, which can be compromised at any point along the way, resulting in malignant transformation and metastasis of tumour cells and resistance to anticancer therapy [56,57]. ...
Tremendous amount of financial resources and manpower have been invested to understand the function of numerous genes that are deregulated during the carcinogenesis process, which can be targeted for anticancer therapeutic interventions. Death-associated protein kinase 1 (DAPK-1) is one of the genes that have shown potential as biomarkers for cancer treatment. It is a member of the kinase family, which also includes Death-associated protein kinase 2 (DAPK-2), Death-associated protein kinase 3 (DAPK-3), Death-associated protein kinase-related apoptosis-inducing kinase 1 (DRAK-1) and Death-associated protein kinase-related apoptosis-inducing kinase 2 (DRAK-2). DAPK-1 is a tumour-suppressor gene that is hypermethylated in most human cancers. Additionally, DAPK-1 regulates a number of cellular processes, including apoptosis, autophagy and the cell cycle. The molecular basis by which DAPK-1 induces these cell homeostasis-related processes for cancer prevention is less understood; hence, they need to be investigated. The purpose of this review is to discuss the current understanding of the mechanisms of DAPK-1 in cell homeostasis-related processes, especially apoptosis, autophagy and the cell cycle. It also explores how the expression of DAPK-1 affects carcinogenesis. Since deregulation of DAPK-1 is implicated in the pathogenesis of cancer, altering DAPK-1 expression or activity may be a promising therapeutic strategy against cancer.
... 7 Dysregulation of apoptosis and growth factor abnormalities cause cancer. 8 Hepatocellular carcinoma (HCC) is one of the most familiar diseases in the world, the third leading cause of cancer-related death, and accounts for more than 80,000 fatalities annually. 9 Several potential drugs were used as promising therapeutic targets for HCC, with varying degrees of inhibition of HCC. ...
... This parallels a recent publication stating CNPs triggered cell death via p53's direct mediation. 8 As mentioned in the research, cancer develops by inhibiting cell death and uncontrolled cell proliferation. That is due to the resistance of tumor cells to apoptosis and to survive and metastasize. ...
Objectives:
Curcumin has antioxidant and antiproliferative properties, and its therapeutic effect must be considered. Nanocurcumin capsules showed a potential increase against in vitro biological cancer. This study sought to determine how curcumin nanoparticles and nanocapsules affected the expression of p53, Bcl-2, Bax, and Bax in a liver cancer cell line (Hep-G2). Mechanisms of apoptosis were also examined in this cell line.
Methods:
This study used quantitative real-time polymerase chain reaction (qRT-PCR) to analyze the p53, Bcl-2, Bax, and Caspase-3 gene pathways and to evaluate the molecular mechanisms responsible for the efficacy of curcumin nanoparticles (CNPs) and curcumin nanocapsules (CNCs) against liver cell lines. Flow cytometry was used to check for signs of apoptosis and the cell cycle.
Results:
Curcumin nanocapsules produced by the ball milling process at 90 min significantly boosted the populations of apoptotic cells in a dose- and time-dependent manner. The mRNA expression analysis revealed that the proapoptotic Bax, Caspase-3, and the tumor suppressor gene p53 were upregulated throughout the process started by curcumin nanocapsules and decreased in the Bcl-2/Bax ratio.
Conclusion:
This research provides a fresh understanding of the molecular mechanisms behind the liver cancer-fighting abilities of curcumin nanoparticles. Curcumin nanocapsules produced through a unique mechanical technique can be used as an anticancer agent.
... Caspases are implicated in a variety of human diseases, including cancer and inflammatory disorders, and considerable attempts to better understand how these enzymes work and might be managed are underway (McIlwain et al. 2013). Deregulation of caspase results in abnormal apoptosis which eventually leads to decreased apoptosis, irregular growth of cancer cells, and carcinogenesis (Farghadani and Naidu 2021). The dysregulation of caspase can occur via different mechanisms which include inhibition by apoptotic protein, dimerization blockage of initiator caspases etc. (Boice and Bouchier-Hayes 2020). ...
... The deficiency of initiator apoptosis has been linked to the formation and progression of cancer. Majorly, altered expression of caspase-8, -9 and -10 is known to be involved in the progress of carcinogenesis (Farghadani and Naidu 2021). In addition to this, studies have reported the dysregulation of single or multiple caspases which contributes to tumour cell growth and development. ...
The vital role of structurally and functionally stable vasculature in engineered tissues is well-established in regenerative medicine. Large-volume, natural, and synthetic tissue constructs require a high degree of perfusion and nutrient diffusion to meet the physiological demands of the encapsulated cells. Additionally, cancer tissue models fabricated using various scaffolds and matrices also need to incorporate tumor-mimetic abnormal vasculature to study the influence of angiogenesis on tumor growth, progression, and anti-cancer drug delivery. In this chapter, prominent hydrogel-based matrices that have been developed for vascular tissue engineering as well as modeling of the tumor vasculature and angiogenesis are discussed. Various microenvironmental considerations (including biophysical and biochemical characteristics of the matrix) required for emulating vascular regeneration as well as tumor angiogenesis are described. A wide range of hydrogel-based models (including natural, synthetic and hybrid materials) and associated biofabrication strategies (spanning molecular design to macroscale materials processing) for creating vascularized scaffolds are elaborated. Overall, this chapter provides an overview to the reader on creation of engineered scaffolds for implementation in tissue vascularization and repair and in disease models for future applications in drug testing.
Nowadays, it is well recognized that apoptosis, as a highly regulated cellular process, plays a crucial role in various biological processes, such as cell differentiation. Dysregulation of apoptosis is strongly implicated in the pathophysiology of numerous disorders, making it essential to comprehend its underlying mechanisms. One key factor that has garnered significant attention in the regulation of apoptotic pathways is HMG-CoA reductase degradation protein 1, also known as HRD1. HRD1 is an E3 ubiquitin ligase located in the endoplasmic reticulum (ER) membrane. Its primary role involves maintaining the quality control of ER proteins by facilitating the ER-associated degradation (ERAD) pathway. During ER stress, HRD1 aids in the elimination of misfolded proteins that accumulate within the ER. Therefore, HRD1 plays a pivotal role in the regulation of apoptotic pathways and maintenance of ER protein quality control. By targeting specific protein substrates and affecting apoptosis-related pathways, HRD1 could be an exclusive therapeutic target in different disorders. Dysregulation of HRD1-mediated processes contributes significantly to the pathophysiology of various diseases. The purpose of this review is to assess the effect of HRD1 on the pathways related to apoptosis in various diseases from a therapeutic perspective.
Graphical Abstract
Cells undergoing initiation of carcinogenesis and regeneration often share most of the molecular pathways. Consequently, cancer treatment may compromise regenerative processes and vice versa may modulate the initiation or inhibition of carcinogenesis. This chapter thus focuses on categorically identifying and exploring the molecules, molecular pathways and their respective roles in both cancer development and regeneration, and on delineating them accordingly. Besides that, the role of inflammation, DNA methylation and epigenetic regulation, autophagy, as well as growth factors are discussed for both the processes. Moreover, focus was placed on identification of exclusive molecular targets, choosing therapeutic molecules as well as selecting suitable therapeutic strategies for achieving the desired results. In conclusion, pathway-targeting therapies, such as RNA therapy, gene therapy, lipid-based therapy and polymer-based therapies, can maintain exclusivity and may be the future of cancer therapy and regenerative medicine.
