Mitophagy: Link to cancer development and therapy Kulikov, Andrey V.; Luchkina, Ekaterina A.; Gogvadze, Vladimir ...
Biochemical and biophysical research communications,
01/2017, Letnik:
482, Številka:
3
Journal Article
Recenzirano
Mitophagy, the selective degradation of mitochondria via the autophagic pathway, is a vital mechanism of mitochondrial quality control in cells. Mitophagy is responsible for the removal of ...malfunctioning or damaged mitochondria, which is essential for normal cellular physiology and tissue development. Pathways involved in the regulation of mitophagy, tumorigenesis, and cell death are overlapping in many cases and may be triggered by common upstream signals, which converge at the mitochondria. The failure to properly modulate mitochondrial turnover in response to oncogenic stresses can either stimulate or suppress tumorigenesis. Thus, the analysis of crosstalk among the processes of mitophagy, cell death and tumorigenesis is important for the identification of targets responsible for the stimulation of cell death and selective elimination of cancer cells. In the present review, we analyze the mechanisms of mitophagy regulation, the pathways underlying the utilization of damaged mitochondria, and how intervention with mitophagy can affect tumor cell resistance to treatment.
•Mitophagy, the selective degradation of mitochondria via the autophagic pathway.•Intervention with mitophagy can affect tumor cell resistance to treatment.•A cross-talk between mitophagy, tumorigenesis and cell death exists.
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.
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.
Release of cytochrome
c from mitochondria is a key initiative step in the apoptotic process, although the mechanisms regulating permeabilization of the outer mitochondrial membrane and the release of ...intermembrane space proteins remain controversial. Here, we discuss possible scenarios of the outer membrane permeabilization. The mechanisms by which the intermembrane space proteins are released from mitochondria depend presumably on cell type and on the nature of the apoptotic stimulus. The variety of mechanisms that can lead to outer membrane permeabilization might explain diversities in the response of mitochondria to numerous apoptotic stimuli in different types of cells.
DNA damage-induced apoptosis Norbury, Chris J; Zhivotovsky, Boris
Oncogene,
04/2004, Letnik:
23, Številka:
16
Journal Article
Recenzirano
Odprti dostop
Unicellular organisms respond to the presence of DNA lesions by activating cell cycle checkpoint and repair mechanisms, while multicellular animals have acquired the further option of eliminating ...damaged cells by triggering apoptosis. Defects in DNA damage-induced apoptosis contribute to tumorigenesis and to the resistance of cancer cells to a variety of therapeutic agents. The intranuclear mechanisms that signal apoptosis after DNA damage overlap with those that initiate cell cycle arrest and DNA repair, and the early events in these pathways are highly conserved. In addition, multiple independent routes have recently been traced by which nuclear DNA damage can be signalled to the mitochondria, tipping the balance in favour of cell death rather than repair and survival. Here, we review current knowledge of nuclear DNA damage signalling, giving particular attention to interactions between these nuclear events and apoptotic processes in other intracellular compartments.
Non-coding RNAs (ncRNAs) are a group of RNA molecules, such as small nucleolar RNAs, circular RNAs (circRNAs), microRNAs (miRNAs) and long-noncoding RNAs (ncRNAs), that do not encode proteins. ...Although their biofunctions are not well-understood, many regulatory ncRNAs appear to be highly involved in regulating the transcription and translation of several genes that have essential biological roles including cell differentiation, cell death, metabolism, tumorigenesis and so on. A growing number of studies have revealed the associations between dysregulated ncRNAs and caspases involved in cell death in numerous human diseases. As one of the initiator and executor caspases, caspase-2 is the most evolutionally conserved caspase in mammals, exerting both apoptotic and non-apoptotic functions. A great deal of studies has shown the involvement of caspase-2 as a tumor suppressor in multiple oncogene-driven cancers, and yet a comprehensive understanding of its biological roles remains largely unknown. In this review, we highlight a compilation of studies focused on the interaction between caspase-2 and miRNAs/lncRNAs in the context of different diseases in order to deepen our knowledge on the regulatory biofunctions of caspase-2 and, furthermore, provide more insight into understanding the role that ncRNAs/caspase-2 axis plays in the development of human diseases.
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.
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.
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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