Nutraceuticals as Supplements for Cancer Prevention
Sheeba Varghese Gupta, Yashwant V. Pathak in Advances in Nutraceutical Applications in Cancer, 2019
The mechanism of cannabinoids in cancer prevention is predominantly attributed to the inhibition of cancer cell proliferation and the induction of apoptosis. Agonism of CB1 and CB2 receptors cause apoptosis by stimulating ceramide synthesis. Increases in ceramide concentration causes activation of the endoplasmic reticulum (ER) stress-related signaling pathway, an evolutionarily conserved response, termed the unfolded protein response (UPR). This pathway, when activated, causes increased expression of the highly mobile transcriptional regulation factor, p8. The p8 is a key player in the cellular stress response [80]. The expression of p8 mediates early cancer development by stopping the translation of cancer cells and degrading mutated proteins. Activation of p8 results in activation of downstream targets including activating transcription factor 4 (ATF4), C/EBP homologous protein (CHOP), and tribbles homologue 3 (TRIB3). Activation of TRIB3 specifically causes inhibition of Akt, subsequent inhibition of mTORC1, and finally autophagy [70,81] (Figure 2.5).
Inflammatory bowel disease
Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald in Principles of Mucosal Immunology, 2020
Autophagy is a cellular process that is classically responsible for the degradation of damaged organelles or long-lived proteins. It is activated by a variety of conditions associated with starvation and cellular stress such as that associated with the unfolded protein response as a consequence of stress caused by the accumulation of misfolded protein within the endoplasmic reticulum (ER) as well as the presence of cell-associated bacteria. Genes associated with bacterial sensing such as those encoding NOD2 (as discussed) and intelectin-1 have been associated with Crohn's disease, genes associated with autophagy such as autophagy-related gene 16 like-1 (ATG16L1) and that encoding immunity-related guanosine triphosphatase (IRGM) have been associated with Crohn's disease, and genes associated with ER stress such as those encoding X-box binding protein-1 (XBP1) and orsomucoid 1-like 3 (ORMDL3) have also been associated with both Crohn's disease and ulcerative colitis. Although the functional mechanisms for these susceptibilities are incompletely understood, as discussed later, they highlight the primary importance of innate immunity and the intestinal epithelium in the immunopathogenesis of IBD.
The Role of Nanoparticles in Cancer Therapy through Apoptosis Induction
Hala Gali-Muhtasib, Racha Chouaib in Nanoparticle Drug Delivery Systems for Cancer Treatment, 2020
Endoplasmic reticulum (ER) is an organelle implicated in the secretion and correct folding of proteins, Ca2+ balance, as well as maintaining the quality control of proteins and cell homeostasis. In different situations, such as physiological or pathological conditions, the demand for folding proteins is increased, resulting in an elevation of unfolded or misfolded protein levels in the ER lumen. This burden on the ER is known as the ER stress. To cope with the stress, the unfolded protein response (UPR) is activated. If the URR cannot restore the stress, the UPR mediates apoptosis [38]. The studies have shown that two main pathways, a transcription factor- and a caspase-dependent signaling pathway, mediate ER stress-dependent apoptosis. The UPR mediators, such as transcription factor GADD153/CHOP, can disrupt the balance between BCL-2 and BAX, resulting in the induction of apoptosis. ER stress-induced apoptosis also occurs through the activation of CASP-12, independent of mitochondrial and death receptors pathways (Fig. 3.1) [39]. There is contradictory information about ER stress-mediated apoptosis. Some have demonstrated that UPR mediates apoptosis through CASP-12, while some claimed that CASP-12 is not related to UPR-mediated apoptosis, rather it is dependent on the mitochondrial apoptotic pathway [40, 41]. Interestingly, in most humans, CASP12 appears to be nonfunctional [42], and the ER-resident of CASP-4 is known to be implicated in ER stress-induced apoptosis [43–45].
(off)Targeting UPR signaling: the race toward intervening ER proteostasis
Published in Expert Opinion on Therapeutic Targets, 2018
Rodrigo Pérez-Arancibia, Alexis Rivas, Claudio Hetz
The secretory and folding capacity of the cell is constantly challenged by physiological demands and pathological perturbations that disturb the process of protein synthesis and maturation. To adjust the protein folding capacity of the endoplasmic reticulum (ER) according to the need, cells engage a dynamic intracellular signaling pathway known as the unfolded protein response (UPR). Homeostatic activation of the UPR enforces adaptive programs that improve key aspects of the secretory pathway, whereas chronic ER stress results in apoptosis. The generation of genetically modified mice for specific UPR components has uncovered the relevance of the pathway to the physiology of different organs and cell types. Due to the fundamental role of the UPR in controlling protein folding, abnormal levels of ER stress have been associated with a variety of pathologies involving specialized secretory cells, in addition to diseases linked to protein misfolding and aggregation, highlighting cancer, autoimmunity, diabetes, obesity, and neurodegeneration [1].
Cinobufagin induces acute promyelocytic leukaemia cell apoptosis and PML-RARA degradation in a caspase-dependent manner by inhibiting the β-catenin signalling pathway
Published in Pharmaceutical Biology, 2022
Yaoyao Bian, Mei Xue, Xinlong Guo, Wenjuan Jiang, Ye Zhao, Zhaofeng Zhang, Xian Wang, Yongkang Hu, Qi Zhang, Wenliang Dun, Liang Zhang
Several natural products that induce ER stress and apoptosis, thereby exerting antitumor effects, have been discovered in recent years (Kim and Kim 2018). ER stress caused by intracellular misfolded and unfolded proteins can activate unfolded protein response via three pathways: the IRE 1, PERK, ATF6 (Pak et al. 2019). Simultaneously, ER stress is accompanied by an imbalance in cytoplasmic calcium homeostasis. Notably, we found that CBG activated the PERK-eIF2α-ATF4 pathway, causing an increase in intracellular Ca2+, which confirmed that CBG triggered ER stress in NB4 and NB4-R1 cells. ER stress-induced apoptosis is mainly mediated by CHOP which is activated by the PERK-eIF2α-ATF4 axis. In the present study, CHOP expression was increased. Particularly, CHOP regulates Bax and Bcl-2 expression (Alshammari et al. 2021; Chen et al. 2021; Hardy et al. 2021; Zheng et al. 2021), activates downstream caspase, and induces apoptosis (Hsu et al. 2018; Huang et al. 2018; Isobe et al. 2019). In the present study, we found that the Bax/Bcl-2 ratio increased following CBG administration.
Morin supplementation modulates PERK branch of UPR and mitigates 1,2-dimethylhydrazine-induced angiogenesis and oxidative stress in the colon of experimental rats
Published in Toxicology Mechanisms and Methods, 2020
Sharada H. Sharma, Jayasurya Suresh Kumar, Shenbagam Madhavan, Sangeetha Nagarajan
Unfolded protein response (UPR) is a regulatory system that responds to the burden of unfolded proteins in the lumen of endoplasmic reticulum (ER) stress by activating intracellular signal transduction pathways (Walter and Ron 2011). In several physiological milieus, the fate of cell survival and cell death is controlled by the intracellular redox conditions and the UPR (Eletto et al. 2014). Previous investigations have shown that PERK (protein kinase PKR-like ER kinase) branch of the UPR regulates angiogenesis and it plays a major role in solid tumor progression (Ma and Hendershot 2004; Mahadevan and Zanetti 2011). In response to UPR activation, PERK phosphorylates the eukaryotic translation initiation factor eIF2α, which in turn causes general attenuation of protein synthesis while enhancing the translation of activating transcription factor 4 (ATF4), which subsequently induces its target genes, including C/EBP homologous protein (CHOP), a transcription factor involved in the induction of proteins involved in apoptosis and antioxidants, i.e. those involved in resistance to oxidative stress (Harding et al. 2000, 2003). Our recent report showed that administration of DMH has shown to increase the colonic expression of GRP78, a chief regulator of UPR associated with decreased expression of phosphorylated PERK, eIFα and CHOP in experimental rats (Sharma et al. 2018b). Further, it has been shown that Nrf2 can be directly phosphorylated and stabilized by PERK downstream of ER stress (Cullinan et al. 2003).
Related Knowledge Centers
- Cellular Stress Response
- Prion
- Protein
- Protein Folding
- Yeast
- Apoptosis
- Endoplasmic Reticulum
- Lumen
- Translation
- Chaperone