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.
Mitochondria in addition to be a main cellular power station, are involved in the regulation of many physiological processes, such as generation of reactive oxygen species, metabolite production and ...the maintenance of the intracellular Ca
homeostasis. Almost 100 years ago Otto Warburg presented evidence for the role of mitochondria in the development of cancer. During the past 20 years mitochondrial involvement in programmed cell death regulation has been clarified. Moreover, it has been shown that mitochondria may act as a switchboard between various cell death modalities. Recently, accumulated data have pointed to the role of mitochondria in the metastatic dissemination of cancer cells. Here we summarize the modern knowledge concerning the contribution of mitochondria to the invasion and dissemination of tumor cells and the possible mechanisms behind that and attempts to target metastatic cancers involving mitochondria.
Cancer therapy is aimed at the elimination of tumor cells and acts via the cessation of cell proliferation and induction of cell death. Many research publications discussing the mechanisms of ...anticancer drugs use the terms "cell death" and "apoptosis" interchangeably, given that apoptotic pathways are the most common components of the action of targeted and cytotoxic compounds. However, there is sound evidence suggesting that other mechanisms of drug-induced cell death, such as necroptosis, ferroptosis, autophagy, etc. may significantly contribute to the fate of cancer cells. Molecular cross-talks between apoptotic and nonapoptotic death pathways underlie the successes and the failures of therapeutic interventions. Here we discuss the nuances of the antitumor action of two groups of the widely used anticancer drugs, i.e., platinum salts and taxane derivatives. The available data suggest that intelligent interference with the choice of cell death pathways may open novel opportunities for cancer treatment.
In order to maintain a functional mitochondrial network, cells have developed a quality control mechanism, namely mitophagy. This process can be induced through different pathways. The most studied ...is the so-called PINK1/Parkin pathway, which is associated with ubiquitylation of several mitochondrial proteins that were initially found to be related to Parkinson’s disease. Another type of mitophagy is known as receptor-mediated mitophagy, which includes proteins, such as BNIP3 and BNIP3L, also known as Nix. Through these two mechanisms, mitophagy fulfills its functions and maintains cellular homeostasis. Here, we summarize the current knowledge about the mechanisms of mitophagy regulation and their interplay with cancer progression as well as anticancer treatment.
For over 20 years, it has been a dogma that once the integrity of mitochondria is disrupted and proapoptotic proteins that are normally located in the intermembrane space of mitochondria appeared in ...the cytoplasm, the process of cell death becomes inevitable. However, it has been recently shown that upon removal of the death signal, even at the stage of disturbance in the mitochondria, cells can recover and continue to grow. This phenomenon was named anastasis. Here, we will critically discuss the present knowledge concerning the mechanisms of cell death reversal, or development of anastasis, methods for its detection, and what role signaling from different intracellular compartments plays in anastasis stimulation.
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.
Multiple cell death mechanisms operate in both uni- and multicellular organisms. Hence, research during the past forty years has revealed that apoptosis is not the only cell death program involved in ...the regulation of tissue homeostasis and the removal of unwanted cells in biological organisms. While the molecular pathways of apoptosis and necrosis are now relatively well established, the precise mechanisms of other cell death modalities, and their cross-talk, require additional study. This is particularly important, since many human disorders can be attributed, directly or indirectly, to defective cell death mechanisms. In this review we shall discuss the characteristics and cross-talk between various modes of cell death and their role in cell death-related disorders, notably, neurodegenerative disease and cancer.
Autophagy is a catabolic process involved in the turnover of organelles and macromolecules which, depending on conditions, may lead to cell death or preserve cell survival. We found that some lung ...cancer cell lines and tumor samples are characterized by increased levels of lipidated LC3. Inhibition of autophagy sensitized non-small cell lung carcinoma (NSCLC) cells to cisplatin-induced apoptosis; however, such response was attenuated in cells treated with etoposide. Inhibition of autophagy stimulated ROS formation and treatment with cisplatin had a synergistic effect on ROS accumulation. Using genetically encoded hydrogen peroxide probes directed to intracellular compartments we found that autophagy inhibition facilitated formation of hydrogen peroxide in the cytosol and mitochondria of cisplatin-treated cells. The enhancement of cell death under conditions of inhibited autophagy was partially dependent on caspases, however, antioxidant NAC or hydroxyl radical scavengers, but not the scavengers of superoxide or a MnSOD mimetic, reduced the release of cytochrome c and abolished the sensitization of the cells to cisplatin-induced apoptosis. Such inhibition of ROS prevented the processing and release of AIF (apoptosis-inducing factor) and HTRA2 from mitochondria. Furthermore, suppression of autophagy in NSCLC cells with active basal autophagy reduced their proliferation without significant effect on the cell-cycle distribution. Inhibition of cell proliferation delayed accumulation of cells in the S phase upon treatment with etoposide that could attenuate the execution stage of etoposide-induced apoptosis. These findings suggest that autophagy suppression leads to inhibition of NSCLC cell proliferation and sensitizes them to cisplatin-induced caspase-dependent and -independent apoptosis by stimulation of ROS formation.
The majority of anticancer drugs are DNA-damaging agents, and whether or not they may directly target mitochondria remains unclear. In addition, tumors such as neuroblastoma exhibit addiction to ...glutamine in spite of it being a nonessential amino acid. Our aim was to evaluate the direct effect of widely used anticancer drugs on mitochondrial activity in combination with glutamine withdrawal, and possible apoptotic effects of such interaction. Our results revealed that etoposide inhibits mitochondrial respiratory chain Complex I causing the leakage of electrons and the superoxide radical formation. However, it was not sufficient to induce apoptosis, and apoptotic manifestation was detectable only alongside the withdrawal of glutamine, a precursor for antioxidant glutathione. Thus, the simultaneous depletion of glutathione and destabilization of mitochondria by ROS can compromise the barrier properties of the mitochondrial membrane, leading to cytochrome
c
release and the activation of the mitochondrial apoptotic pathway. Thus, the depletion of antioxidants or the inhibition of the pathways responsible for cellular antioxidant response can enhance mitochondrial targeting and strengthen antitumor therapy.
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