Cell Death Signaling and Anticancer Therapy

Galluzzi, Lorenzo; Vitale, Ilio; Vacchelli, Erika; Kroemer, Guido

doi:10.3389/fonc.2011.00005

Cited by 47 publications

(37 citation statements)

References 247 publications

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“…Nowadays, the increased resistance of more and more cancer cells to pro-apoptotic agents and the side effects mediated by apoptosis in normal tissues largely hinder the improvement of anti-cancer therapies. Conversely, cancer cells seem to be intrinsically more sensitive to mitotic catastrophe than normal cells (43,44). Therefore, our finding indicates that eEF2K could be a potential target for drug development to improve cancer-killing efficacy and simultaneously protect normal cells from apoptosis.…”

Section: Eef2k In Stem Cell Survivalmentioning

confidence: 78%

Paradoxical Roles of Elongation Factor-2 Kinase in Stem Cell Survival

Liao

Chu

et al. 2016

Journal of Biological Chemistry

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Protein synthesis inhibition is an immediate response during stress to switch the composition of protein pool in order to adapt to the new environment. It was reported that this response could be either protective or deleterious. However, how cells choose to live or die upon protein synthesis inhibition is largely unknown. Previously, we have shown that elongation factor-2 kinase (eEF2K), a protein kinase that suppresses protein synthesis during elongation phase, is a positive regulator of apoptosis both in vivo and in vitro. Consistently, here we report that knock-out of eEF2K protects mice from a lethal dose of whole-body ionizing radiation at 8 Gy by reducing apoptosis levels in both bone marrow and gastrointestinal tracts. Surprisingly, similar to the loss of p53, eEF2K deficiency results in more severe damage to the gastrointestinal tract at 20 Gy with the increased mitotic cell death in small intestinal stem cells. Furthermore, using epithelial cell lines, we showed that eEF2K is required for G 2 /M arrest induced by radiation to prevent mitotic catastrophe in a p53-independent manner. Specifically, we observed the elevation of Akt/ERK activity as well as the reduction of p21 expression in Eef2k ؊/؊ cells. Therefore, eEF2K also provides a protective strategy to maintain genomic integrity by arresting cell cycle in response to stress. Our results suggest that protective versus pro-apoptotic roles of eEF2K depend on the type of cells: eEF2K is protective in highly proliferative cells, such as small intestinal stem cells and cancer cells, which are more susceptible to mitotic catastrophe.

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Section: Eef2k In Stem Cell Survivalmentioning

confidence: 78%

Paradoxical Roles of Elongation Factor-2 Kinase in Stem Cell Survival

Liao

Chu

et al. 2016

Journal of Biological Chemistry

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“…Conventional chemotherapy and radiotherapy induce catastrophic cellular stress in cancer cells and eliminate them by apoptosis through the activation of the p53-dependent checkpoint mechanism (Deckbar et al, 2011;Galluzzi et al, 2011). However, these treatments often fail to eradicate cancer stem cells, possibly because these cells acquire mutations that inactivate the apoptotic machinery or simply undergo cell division infrequently.…”

Section: Introductionmentioning

confidence: 99%

“…Programmed cell death plays a pivotal role during the maintenance of homeostasis and constitutes the molecular basis for various chemotherapies and radiotherapies for cancers (Fuchs and Steller, 2011;Galluzzi et al, 2011). Necrosis frequently serves as the main alternative cell death modality to eliminate apoptosisdeficient cells under certain physiological conditions (Vandenabeele et al, 2010;Han et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

A novel Fizzy/Cdc20-dependent mechanism suppresses necrosis in neural stem cells

et al. 2014

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Cancer stem cells likely survive chemotherapy or radiotherapy by acquiring mutations that inactivate the endogenous apoptotic machinery or by cycling slowly. Thus, knowledge about the mechanisms linking the activation of an alternative cell death modality and the cell cycle machinery could have a transformative impact on the development of new cancer therapies, but the mechanisms remain completely unknown. We investigated the regulation of alternative cell death in Drosophila larval brain neural stem cells (neuroblasts) in which apoptosis is normally repressed. From a screen, we identified two novel loss-of-function alleles of the Cdc20/fizzy (fzy) gene that lead to premature brain neuroblast loss without perturbing cell proliferation in other diploid cell types. Fzy is an evolutionarily conserved regulator of anaphase promoting complex/cyclosome (APC/C). Neuroblasts carrying the novel fzy allele or exhibiting reduced APC/C function display hallmarks of necrosis. By contrast, neuroblasts overexpressing the non-degradable form of canonical APC/C substrates required for cell cycle progression undergo mitotic catastrophe. These data strongly suggest that Fzy can elicit a novel pro-survival function of APC/C by suppressing necrosis. Neuroblasts experiencing catastrophic cellular stress, or overexpressing p53, lose Fzy expression and undergo necrosis. Co-expression of fzy suppresses the death of these neuroblasts. Consequently, attenuation of the Fzydependent survival mechanism functions downstream of catastrophic cellular stress and p53 to eliminate neuroblasts by necrosis. Strategies that target the Fzy-dependent survival mechanism might lead to the discovery of new treatments or complement the pre-existing therapies to eliminate apoptosis-resistant cancer stem cells by necrosis.

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“…Consequently, failure of therapy frequently is a result of resistance against cell death (5). At a clinical level, noninvasive imaging of cell death will allow identification of nonresponding tumors at an early stage after the start of treatment, leading to a timely change in the individualized treatment plan that increases the probability of response and, ultimately, patient survival.…”

mentioning

confidence: 99%

Early Prediction of Tumor Response to Treatment: Preclinical Validation of ^99mTc-Duramycin

et al. 2016

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Noninvasive imaging of cell death can provide an early indication of the efficacy of tumor treatment, aiding clinicians in distinguishing responding patients from nonresponding patients early on. 99m Tcduramycin is a SPECT tracer for cell death imaging. In this study, our aim was to validate the use of 99m Tc-duramycin for imaging the early response of tumors to treatment. Methods: An in vitro binding assay was performed on COLO205 cells treated with 5-fluorouracil (3.1, 31, or 310 μM) and oxaliplatin (0.7 or 7 μM) or radiation (2 or 4.5 Gy). 99m Tc-duramycin cell binding and the levels of cell death were evaluated after treatment. In vivo imaging was performed on 4 groups of CD1-deficient mice bearing COLO205 human colorectal cancer tumors. Each group included 6 tumors. The first group was given irinotecan (100 mg/kg), the second oxaliplatin (5 mg/kg), the third irinotecan (80 mg/kg) plus oxaliplatin (5 mg/kg), and the fourth vehicle (0.9% NaCl and 5% glucose). For radiotherapy studies, COLO205 tumors received 4.5 Gy, 2 fractions of 4.5 Gy in a 24-h interval, pretreatment with an 80 mg/kg dose of irinotecan combined with 2 fractions of 4.5 Gy in a 24-h interval, or no treatment (n 5 5-6/group). Therapy response was evaluated by 99m Tc-duramycin SPECT 24 h after the last dose of therapy. Blocking was used to confirm tracer specificity. Radiotracer uptake in the tumors was validated ex vivo using γ-counting, cleaved caspase-3, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) histology. Results: Chemotherapy and radiotherapy increased 99m Tc-duramycin binding to COLO205 cells in a concentration/ dose-and time-dependent manner, which correlated well with cell death levels (P , 0.05) as analyzed by annexin V and caspase 3/7 activity. In vivo, 99m Tc-duramycin uptake in COLO205 xenografts was increased 2.3-and 2.8-fold (P , 0.001) in mice treated with irinotecan and combination therapy, respectively. Blocking with unlabeled duramycin demonstrated specific binding of the radiotracer. After tumor irradiation with 4.5 Gy, 99m Tc-duramycin uptake in tumors increased significantly (1.24 ± 0.07 vs. 0.57 ± 0.08 percentage injected dose per gram in the unirradiated tumors; P , 0.001). γ-counting of radioactivity in the tumors positively correlated with cleaved caspase-3 (r 5 0.85, P , 0.001) and TUNEL (r 5 0.81, P , 0.001) staining. Conclusion: We demonstrated that 99m Tc-duramycin can be used to image induction of cell death early after chemotherapy and radiotherapy. It holds potential to be translated into clinical use for early assessment of treatment response.

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Cell Death Signaling and Anticancer Therapy

Cited by 47 publications

References 247 publications

Paradoxical Roles of Elongation Factor-2 Kinase in Stem Cell Survival

Paradoxical Roles of Elongation Factor-2 Kinase in Stem Cell Survival

A novel Fizzy/Cdc20-dependent mechanism suppresses necrosis in neural stem cells

Early Prediction of Tumor Response to Treatment: Preclinical Validation of ^99mTc-Duramycin

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Cell Death Signaling and Anticancer Therapy

Cited by 47 publications

References 247 publications

Paradoxical Roles of Elongation Factor-2 Kinase in Stem Cell Survival

Paradoxical Roles of Elongation Factor-2 Kinase in Stem Cell Survival

A novel Fizzy/Cdc20-dependent mechanism suppresses necrosis in neural stem cells

Early Prediction of Tumor Response to Treatment: Preclinical Validation of 99mTc-Duramycin

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Early Prediction of Tumor Response to Treatment: Preclinical Validation of ^99mTc-Duramycin