Apoptosis is a form of programmed cell death that results in the orderly and efficient removal of damaged cells, such as those resulting from DNA damage or during development. Apoptosis can be triggered by signals from within the cell, such as genotoxic stress, or by extrinsic signals, such as the binding of ligands to cell surface death receptors. Deregulation in apoptotic cell death machinery is an hallmark of cancer. Apoptosis alteration is responsible not only for tumor development and progression but also for tumor resistance to therapies. Most anticancer drugs currently used in clinical oncology exploit the intact apoptotic signaling pathways to trigger cancer cell death. Thus, defects in the death pathways may result in drug resistance so limiting the efficacy of therapies. Therefore, a better understanding of the apoptotic cell death signaling pathways may improve the efficacy of cancer therapy and bypass resistance. This review will highlight the role of the fundamental regulators of apoptosis and how their deregulation, including activation of anti-apoptotic factors (i.e., Bcl-2, Bcl-xL, etc) or inactivation of pro-apoptotic factors (i.e., p53 pathway) ends up in cancer cell resistance to therapies. In addition, therapeutic strategies aimed at modulating apoptotic activity are briefly discussed.
Caspase-14 is a recent addition to the caspase family of aspartate proteases involved in apoptotic processes. Human caspase-14 appears to be only weakly processed during apoptosis, and it does not cleave classical caspase substrates. Post partum, caspase-14 is prominently expressed by human keratinocytes and reportedly participates in terminal differentiation of complex epithelia. Here we provide evidence challenging the view that caspase-14 expression or processing is linked exclusively to terminal keratinocyte differentiation. We demonstrate that caspase-14 expression extended to multiple cell lines derived from simple epithelia of the breast, prostate, and stomach. In keratinocytes and breast epithelial cells, caspase-14 expression was upregulated in high-density cultures and during forced suspension culture. These effects were primarily due to transcriptional activation as indicated by reporter gene assays using a 2 kb caspase-14 promoter fragment. Importantly, caspase-14 was not cleaved during forced suspension culture of either cell type although this treatment induced caspase-dependent apoptosis (anoikis). Forced expression of caspase-14 in immortalized human keratinocytes had no effect on cell death in forced suspension nor was the transfected caspase-14 processed in this setting. In contrast to postconfluent and forced suspension culture, terminal differentiation of keratinocytes induced in vitro by Ca 2+ treatment was not associated with increased caspase-14 expression or promoter activity. Our results indicate that (1) caspase-14 is expressed not only in complex but also simple epithelia; (2) cells derived from complex and simple epithelia upregulate caspase-14 expression in conditions of high cell density or lack of matrix interaction and; (3) in both cell types this phenomenon is due to transcriptional regulation.
BackgroundMutations in the p53 oncosuppressor gene are highly frequent in human cancers. These alterations are mainly point mutations in the DNA binding domain of p53 and disable p53 from transactivating target genes devoted to anticancer activity. Mutant p53 proteins are usually more stable than wild-type p53 and may not only impair wild-type p53 activity but also acquire pro-oncogenic functions. Therefore, targeting mutant p53 to clear the hyperstable proteins or change p53 conformation to reactivate wild-type p53 protein functions is a powerful anticancer strategy. Several small molecules have been tested for p53 reactivation in mutant p53-carrying cells while studies exploiting the effect of natural compounds are limited. Capsaicin (CPS) is the major constituent of peppers and show antitumor activity by targeting several molecular pathway, however, its effect on mutant p53 reactivation has not been assessed yet. In this study we aimed at investigating whether mutant p53 could be a new target of capsaicin-induced cell death and the underlying mechanisms.Methodsp53 levels were analysed by western blot upon capsaicin treatment in the presence of the autophagy inhibitor chloroquine. The mutant p53 reactivation was evaluated by chromatin-immunoprecipitation (ChIP) assay and semi-quantitative RT-PCR analyses of wild-type p53 target genes. The specific wild-type p53 activation was determined by using the inhibitor of p53 transactivation function, pifithrin-α and siRNA for p53.ResultsHere, we show that capsaicin induced autophagy that was, at least in part, responsible of mutant p53 protein degradation. Abrogation of mutant p53 by capsaicin restored wild-type p53 activities over mutant p53 functions, contributing to cancer cell death. Similar effects were confirmed in cancer cells bearing tumor-associated p53 mutations and in H1299 (p53 null) with overexpressed p53R175H and p53R273H mutant proteins.ConclusionThese findings demonstrate for the first time that capsaicin may reduce mutant p53 levels and reactivate wild-type p53 protein in mutant p53-carrying cells and the p53 reactivation contributes to capsaicin-induced cell death.
One of the most revolutionary technologies in recent years in the field of molecular biology is CRISPR-Cas9. CRISPR technology is a promising tool for gene editing that provides researchers the opportunity to easily alter DNA sequences and modify gene function. Its many potential applications include correcting genetic defects, treating and preventing the spread of diseases. Cystic fibrosis (CF) is one of the most common lethal genetic diseases caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Although CF is an old acquaintance, there is still no effective/resolutive cure. Life expectancy has improved thanks to the combination of various treatments, but it is generally below average. Recently, a significant number of additional key medications have become licensed in Europe for the CF treatment including CFTR modulators. But innovative genomically-guided therapies have begun for CF and it is predictable that this will lead to rapid improvements in CF clinical disease and survival in the next decades. In this way, CRISPR-Cas9 approach may represent a valid tool to repair the CFTR mutation and hopeful results were obtained in tissue and animal models of CF disease.
1 Acetaminophen, an analgesic and antipyretic drug with weak antiin¯ammatory properties, has been suggested to act as a tissue-selective inhibitor of prostaglandin H synthases (PGHSs) (e.g. COX-1 and COX-2) through its reducing activity, that is in¯uenced by the di erent cellular levels of peroxides. 2 We have studied the e ects of acetaminophen on inducible and constitutive prostanoid biosynthesis in monocytes and platelets in vitro. To discriminate between the inhibitory e ect of the drug on PGHS-isozymes vs PGE-synthases (PGESs), parallel measurements of PGE 2 and thromboxane (TX) B 2 were carried out. Since antioxidant enzymes and cofactors, present in plasma, may a ect acetaminophen-dependent inhibition of prostanoids, comparative experiments in whole blood vs isolated monocytes were performed. 3 Acetaminophen inhibited LPS-induced whole blood PGE 2 and TXB 2 production, in a concentration-dependent fashion [IC 50 mM (95% con®dence intervals): 44 (27 ± 70) and 94 (79 ± 112), respectively]. Therapeutic plasma concentrations (100 and 300 mM) of the drug more profoundly reduced PGE 2 than TXB 2 (71+3 vs 54+4 and 95+0.8 vs 78+2%, respectively, mean+s.e.mean, n=6, P50.01). 4 Di erently, in isolated monocytes stimulated with LPS, both PGE 2 and TXB 2 production was maximally reduced by only 60%. 5 At 100 and 300 mM, the drug caused a similar and incomplete inhibition of platelet PGE 2 and TXB 2 production during whole blood clotting (45+4 vs 54+4 and 75+2 vs 75+1%, respectively, mean+s.e.mean, n=4). 6 In conclusion, therapeutic concentrations of acetaminophen caused an incomplete inhibition of platelet COX-1 and monocyte COX-2 but in the presence of plasma, the drug almost completely suppressed inducible PGE 2 biosynthesis through its inhibitory e ects on both COX-2 and inducible PGES.
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