The members of the Bcl-2 family are the central regulators of various cell death modalities. Some of these proteins contribute to apoptosis, while others counteract this type of programmed cell ...death, thus balancing cell demise and survival. A disruption of this balance leads to the development of various diseases, including cancer. Therefore, understanding the mechanisms that underlie the regulation of proteins of the Bcl-2 family is of great importance for biomedical research. Among the members of the Bcl-2 family, antiapoptotic protein Mcl-1 is characterized by a short half-life, which renders this protein highly sensitive to changes in its synthesis or degradation. Hence, the regulation of Mcl-1 is of particular scientific interest, and the study of Mcl-1 modulators could aid in the understanding of the mechanisms of disease development and the ways of their treatment. Here, we summarize the present knowledge regarding the regulation of Mcl-1, from transcription to degradation, focusing on aspects that have not yet been described in detail.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The maintenance of genome stability is essential for the cell as the integrity of genomic information guaranties reproduction of a whole organism. DNA damage occurring in response to different ...natural and nonnatural stimuli (errors in DNA replication, UV radiation, chemical agents, etc.) is normally detected by special cellular machinery that induces DNA repair. However, further accumulation of genetic lesions drives the activation of cell death to eliminate cells with defective genome. This particular feature is used for targeting fast-proliferating tumor cells during chemo-, radio-, and immunotherapy. Among different cell death modalities induced by DNA damage, apoptosis is the best studied. Nevertheless, nonapoptotic cell death and adaptive stress responses are also activated following genotoxic stress and play a crucial role in the outcome of anticancer therapy. Here, we provide an overview of nonapoptotic cell death pathways induced by DNA damage and discuss their interplay with cellular senescence, mitotic catastrophe, and autophagy.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Among cell death regulators, members of the Bcl-2 family are of interest because they are highly conserved across species and represent promising targets for anticancer therapy. This family and its ...associated proteins include more than 25 members, with either anti- or proapoptotic functions. Although the overall regulation of apoptosis by Bcl-2 family proteins is now well understood, targeted therapy requires careful consideration of individual members of the family and their crosstalk. One of the most studied representatives of the Bcl-2 family is antiapoptotic Mcl-1. After 25 years of investigations, a large amount of data regarding Mcl-1’s regulation and functions has been compiled. In this review, we summarize current knowledge about Mcl-1, focusing on molecular aspects relevant to Mcl-1-targeted therapies.
Recent advances in molecular oncology have led to the development of the BH3 mimetics – small-molecule drugs that neutralize antiapoptotic Bcl-2 family proteins and, thus, favor the mitochondrial pathway of apoptosis.Mcl-1-selective BH3 mimetics are at relatively early stages of drug development, so their adverse effects, including those relating to the nonapoptotic functions of Mcl-1, are poorly understood.Several BH3 mimetics preclude interactions between Mcl-1 and its proapoptotic partners while stabilizing Mcl-1. Understanding of the conformational changes that induce degradation of Mcl-1 would allow the rational design of alternative compounds that would cause a pronounced reduction of its cellular level.In the context of oncology, it is worth examining alternative strategies to target Mcl-1, such as an alternative splicing switch toward a proapoptotic Mcl-1S isoform and indirect antagonism of Mcl-1.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ
Genomic instability underlies genesis and the development of various types of cancer. During tumorigenesis, cancer initiating cells assume a set of features, which allow them to survive and ...proliferate. Different mutations and chromosomal alterations promote a selection of the most aggressive cancer clones that worsen the prognosis of the disease. Despite that caspase-2 was described as a protease fulfilling an initiator and an effector function in apoptosis, it has recently been discovered to play an important role in the maintenance of genomic integrity and normal chromosome configuration. This protein is able to stabilize p53 and affect the level of transcription factors, which activates cell response to oxidative stress. Here we focus on the discussion on the mechanism(s) of how caspase-2 regulates genomic stability and decreases tumorigenesis.
Tumors in caspase-2 knockout mice grow rapidly and contain more cells with chromosomal aberrations in contrast to wild-type littermates.An accumulation of genomic disturbances, such as supernumerary centrosomes, activates caspase-2 via PIDDosome formation that restricts the proliferation of polyploid cells.Active caspase-2 can cleave Mdm2 and promote the stabilization of p53 level in response to centrosome amplification, which promotes genomic instability and cell neoplastic transformation.Caspase-2 helps to maintain genomic stability, decreasing the level of oxidative stress and DNA damage.Caspase-2 acts as tumor suppressor via its ability to eliminate cells with chromosomal perturbations or after mitotic insults.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ
The cleavage of nuclear proteins by caspases promotes nuclear breakdown and, therefore, plays a key role in apoptosis execution. However, the detailed molecular mechanisms of these events remain ...unclear. To get more insights into the mechanisms of nuclear events during apoptosis we set up a rapid fractionation protocol for the separation of the cytoplasmic and nuclear fractions of cells undergoing cisplatin-induced apoptosis. Importantly, nuclear accumulation of effector caspase-3 as well as initiator caspase-2, -8 and -9 was observed using the developed protocol and immunofluorescence microscopy. The detection of caspases and their cleavage products in the nucleus occurred within the same time interval after cisplatin treatment and took place shortly before nuclear fragmentation. The entry of initiator caspases to the nucleus was independent of caspase-3. Given that all three initiator caspases had catalytic activity in the nuclei, our findings indicate that initiator caspases might participate in the proteolysis of nuclear components during apoptosis, promoting its disintegration and apoptotic cell death.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Since their establishment in the early 1970s, the nuclear changes upon apoptosis induction, such as the condensation of chromatin, disassembly of nuclear scaffold proteins and degradation of DNA, ...were, and still are, considered as the essential steps and hallmarks of apoptosis. These are the characteristics of the execution phase of apoptotic cell death. In addition, accumulating data clearly show that some nuclear events can lead to the induction of apoptosis. In particular, if DNA lesions resulting from deregulation during the cell cycle or DNA damage induced by chemotherapeutic drugs or viral infection cannot be efficiently eliminated, apoptotic mechanisms, which enable cellular transformation to be avoided, are activated in the nucleus. The functional heterogeneity of the nuclear organization allows the tight regulation of these signaling events that involve the movement of various nuclear proteins to other intracellular compartments (and vice versa) to initiate and govern apoptosis. Here, we discuss how these events are coordinated to execute apoptotic cell death.
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EMUNI, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UL, UM, UPUK, VKSCE, ZAGLJ
Although the phenomenon of mitotic catastrophe was first described more than 80 years ago, only recently has this term been used to explain a mechanism of cell death linked to delayed mitosis. ...Several mechanisms have been suggested for mitotic catastrophe development and cell fate. Depending on molecular perturbations, mitotic catastrophe can end in three types of cell death, namely apoptosis, necrosis, or autophagy. Moreover, mitotic catastrophe can be associated with different types of cell aging, the development of which negatively affects tumor elimination and, consequently, reduces the therapeutic effect. The effective triggering of mitotic catastrophe in clinical practice requires induction of DNA damage as well as inhibition of the molecular pathways that regulate cell cycle arrest and DNA repair. Here we discuss various methods to detect mitotic catastrophe, the mechanisms of its development, and the attempts to use this phenomenon in cancer treatment.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Cancer is the second leading cause of death worldwide and the morbidity is growing in developed countries. According to WHO, >14 million people per year are diagnosed with cancer and about 8 million ...die. Anti-cancer strategy includes chemo-, immune- and radiotherapy or their combination. Unfortunately, these widely used strategies often have insufficient efficacy and significant toxic effects on healthy cells. Consequently, the improvement of treatment approaches is an important goal. One of promising schemes to enhance the effect of therapy is the restriction of calorie intake or some nutrients. The combination of caloric restriction or its chemical mimetics along with anti-cancer drugs may suppress growth of tumor cells and enhance death of cancer cells. That will allow the dose of therapeutic drugs to be decreased and their toxic effects to be reduced. Here the possibility of using this combinatory therapy as well as the molecular mechanisms underlying this approach will be discussed.
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•Caloric restriction (CR) reduces the risk factors for various diseases, including cancer.•The downregulation of mTORC1 pathway is one of the most advantageous effects of CR.•PRAPα, AMPK, and Sirt1 depress glycolysis and promote ketogenesis in response to CR.•CR and CRMs are able to sensitize different tumors to chemo- or radiotherapy.•The most promising anti-tumor CRMs with approved efficacy are the mTOR inhibitors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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