Eisenberg-Lerner A, Bialik S, Simon HU, Kimchi A.. Life and death partners: apoptosis, autophagy and the cross-talk between them. Cell Death Differ 16: 966-975

Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
Cell death and differentiation (Impact Factor: 8.18). 04/2009; 16(7):966-75. DOI: 10.1038/cdd.2009.33
Source: PubMed


It is not surprising that the demise of a cell is a complex well-controlled process. Apoptosis, the first genetically programmed death process identified, has been extensively studied and its contribution to the pathogenesis of disease well documented. Yet, apoptosis does not function alone to determine a cell's fate. More recently, autophagy, a process in which de novo-formed membrane-enclosed vesicles engulf and consume cellular components, has been shown to engage in a complex interplay with apoptosis. In some cellular settings, it can serve as a cell survival pathway, suppressing apoptosis, and in others, it can lead to death itself, either in collaboration with apoptosis or as a back-up mechanism when the former is defective. The molecular regulators of both pathways are inter-connected; numerous death stimuli are capable of activating either pathway, and both pathways share several genes that are critical for their respective execution. The cross-talk between apoptosis and autophagy is therefore quite complex, and sometimes contradictory, but surely critical to the overall fate of the cell. Furthermore, the cross-talk is a key factor in the outcome of death-related pathologies such as cancer, its development and treatment.

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    • "Autophagy and apoptosis are known to be two important and interconnected stress-response mechanisms [42]. We have shown previously that autophagy occurs in PDT-treated cells [43]. "
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    ABSTRACT: Oxidative stress mediated by photodynamic therapy (PDT) mediates the tumoricidal effect, but has also been shown to induce the expression of pro-survival molecules, such as cyclooxygenase-2 (COX-2), which is involved in tumor recurrences after PDT. However, the molecular mechanism is still not fully understood. In this study, we found that activated p38MAPK could significantly up-regulate the activity and expression of histone acetyltransferase p300 (p300HAT) in A375 and C26 cells treated with ALA and chlorin e6 (Ce6) mediated photodynamic treatment. Colony-formation assay showed PDT-induced cytotoxicity was dramatically elevated in the presence of p300HAT inhibitor anacardic acid (AA). Further studies showed that the increased p300HAT acetylates histone H3 and NF-κB p65 subunit to up-regulate the COX-2 expression, which was reduced by AA or p300HAT shRNA. Using chromatin immunoprecipitation analysis, we found that the augmented acetylation of histone H3 and NF-κB increases their binding to the COX-2 promoter region. These in vitro findings were further verified in mice bearing murine C26 and human A375 tumors treated with liposomal Ce6 mediated PDT. Meanwhile, the combination of PDT and AA resulted in a greater tumor regression in BALB/c mice bearing C26 tumors, compared to PDT only or combined with COX-2 inhibitor. Finally, we demonstrated that suppression of the PDT-induced p300HAT activity also resulted in the decreased expression of survivin, restoring caspase-3 activity and sensitizing PDT-treated cells from autophagy to apoptosis due to the Becline-1 cleavage. This study demonstrates for the first time the molecular mechanisms involved in histone modification induced by PDT-mediated oxidative stress, suggesting that HAT inhibitors may provide a novel therapeutic approach for improving PDT response. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · May 2015 · Free Radical Biology and Medicine
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    • "Apoptosis and autophagy are two evolutionarily conserved processes that maintain homeostasis during stress (Young et al. 2013). Recent evidence indicates that autophagy played an important role in tumor development, cell death and survival (Eisenberg-Lerner et al. 2009). Previously published studies have shown that diff erent types of cancer cells undergo distinct autophagic responses after various anticancer therapies and result in diff erent outcomes (Kondo and Kondo 2006). "
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    ABSTRACT: To prove the occurrence of autophagy after treatment by protoporphyrin IX (PpIX)- mediated sonodynamic therapy (SDT) of human chronic myelogenous leukemia K562 cells as well as its relationship with apoptosis. The 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenylter-trazolium bromide tetrazolium (MTT) assay was adopted to examine cytotoxicity of different treatments. Nuclear morphology changes were observed under a fluorescence microscopy with 4'-6-Diamidino-2-Phenylindole (DAPI) staining. Western blotting was used to analyze the expression of caspase-3, Beclin 1 (BECN 1) and the conversion of LC3-phosphatidylethanolamine conjugate / a cytosolic form of LC3 (LC3 II / I). Fluorescence microscope was used to identify the formation of autophagic vacuoles (AVO) during autophagy. Under optimal conditions, SDT was shown to induce autophagy in K562 cells, which caused the up-regulation of Beclin-1 and the formation of AVO. In addition, pre-treatment of cancer cells with beclin 1-targeted short hairpin RNA (Beclin 1 shRNA) was shown to reduce the level of LC3-II accumulation and staining with punctate spots of monodansylcadaverine (MDC) staining. Besides, the cytotoxic effect of SDT was significantly increased by Beclin 1 shRNA. Furthermore, studies showed a marked effect on the apoptosis of cells by Beclin 1 shRNA to sonodamage with increased DAPI staining and caspase-3 cleavage. These results demonstrated that SDT significantly induced autophagy of K562 cells, probably to protect the K562 cells from sonodamage.
    Full-text · Article · Mar 2015 · International Journal of Radiation Biology
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    • "Finally, autophagy, commonly described as type II programmed cell death, could also be responsible for causing germ cell death. Autophagy is a process in which cells are phagocytosed by vesicles, degraded by lysosomes, and the resulting cellular components recycled for energy generation (Eisenberg-Lerner et al., 2009; Zhang et al., 2012). When this pathway is activated by heat stress, the cytosolic form of light chain 3 (LC3B-I) is modified into a membrane-bound form (LC3B-II), and the ubiquitin-like conjugation system is activated as well. "
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    ABSTRACT: The process of spermatogenesis is temperature-dependent and occurs optimally at temperatures slightly lower than that of the body. Adequate thermoregulation is imperative to maintain testicular temperatures at levels lower than that of the body core. Raised testicular temperature has a detrimental effect on mammalian spermatogenesis and the resultant spermatozoa. Therefore, thermoregulatory failure leading to heat stress can compromise sperm quality and increase the risk of infertility. In this paper, several different types of external and internal factors that may contribute towards testicular heat stress are reviewed. The effects of heat stress on the process of spermatogenesis, the resultant epididymal spermatozoa and on germ cells, and the consequent changes in the testis are elaborated upon. We also discuss the molecular response of germ cells to heat exposure and the possible mechanisms involved in heat-induced germ cell damage, including apoptosis, DNA damage and autophagy. Further, the intrinsic and extrinsic pathways that are involved in the intricate mechanism of germ cell apoptosis are explained. Ultimately, these complex mechanisms of apoptosis lead to germ cell death.
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