Regression of Solid Tumors by Induction of MazF, a Bacterial mRNA Endoribonuclease

Shimazu, Tsutomu; Mirochnitchenko, Oleg; Phadtare, Sangita; Inouye, Masayori

doi:10.1159/000365509

Cited by 13 publications

(9 citation statements)

References 20 publications

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“…TAs have also been harnessed as tools for biotechnology and molecular biology such as in the development of positive selection plasmid vectors (Stieber et al, 2008 ; Unterholzner et al, 2013 ). The discovery of their functionality in eukaryotic cells have opened up interesting avenues for research and development including as anticancer and antiviral gene therapies, and as a containment system for genetically modified organisms (de la Cueva-Méndez et al, 2003 ; Chono et al, 2011 ; de la Cueva-Méndez and Pimentel, 2013 ; Shimazu et al, 2014 ; Wieteska et al, 2014 ; Chan et al, 2015 ; Preston et al, 2015 ; Yeo et al, 2016 ). With more TAs being discovered and characterized in the coming months and years ahead, our understanding of their variety and complexity, particularly in the regulatory circuits of these small genetic loci, will be greatly enhanced.…”

Section: Discussionmentioning

confidence: 99%

Keeping the Wolves at Bay: Antitoxins of Prokaryotic Type II Toxin-Antitoxin Systems

Chan

Espinosa

Yeo

2016

Front. Mol. Biosci.

119

121

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In their initial stages of discovery, prokaryotic toxin-antitoxin (TA) systems were confined to bacterial plasmids where they function to mediate the maintenance and stability of usually low- to medium-copy number plasmids through the post-segregational killing of any plasmid-free daughter cells that developed. Their eventual discovery as nearly ubiquitous and repetitive elements in bacterial chromosomes led to a wealth of knowledge and scientific debate as to their diversity and functionality in the prokaryotic lifestyle. Currently categorized into six different types designated types I–VI, type II TA systems are the best characterized. These generally comprised of two genes encoding a proteic toxin and its corresponding proteic antitoxin, respectively. Under normal growth conditions, the stable toxin is prevented from exerting its lethal effect through tight binding with the less stable antitoxin partner, forming a non-lethal TA protein complex. Besides binding with its cognate toxin, the antitoxin also plays a role in regulating the expression of the type II TA operon by binding to the operator site, thereby repressing transcription from the TA promoter. In most cases, full repression is observed in the presence of the TA complex as binding of the toxin enhances the DNA binding capability of the antitoxin. TA systems have been implicated in a gamut of prokaryotic cellular functions such as being mediators of programmed cell death as well as persistence or dormancy, biofilm formation, as defensive weapons against bacteriophage infections and as virulence factors in pathogenic bacteria. It is thus apparent that these antitoxins, as DNA-binding proteins, play an essential role in modulating the prokaryotic lifestyle whilst at the same time preventing the lethal action of the toxins under normal growth conditions, i.e., keeping the proverbial wolves at bay. In this review, we will cover the diversity and characteristics of various type II TA antitoxins. We shall also look into some interesting deviations from the canonical type II TA systems such as tripartite TA systems where the regulatory role is played by a third party protein and not the antitoxin, and a unique TA system encoding a single protein with both toxin as well as antitoxin domains.

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Section: Discussionmentioning

confidence: 99%

Keeping the Wolves at Bay: Antitoxins of Prokaryotic Type II Toxin-Antitoxin Systems

Chan

Espinosa

Yeo

2016

Front. Mol. Biosci.

119

121

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“…More recently, reversion of induced solid tumours in mice has been reported by employment of an engineered version of the MazF toxin; nevertheless, the rate of success in reversion was around 50%, probably due to loss of functional toxin (Shimazu et al. , 2014 ). Such a loss of activity was not observed for toxins VapC from M. tuberculosis or PasB from plasmid pTF-FC2 of Thiobacillus ferrooxidans when expressed into human cancer cells (Wieteska et al.…”

Section: Toxicity To Eukaryotic Cellsmentioning

confidence: 99%

One cannot rule them all: Are bacterial toxins-antitoxins druggable?

Chan

Balsa²,

Espinosa

2015

FEMS Microbiology Reviews

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Type II (proteic) toxin–antitoxin (TA) operons are widely spread in bacteria and archaea. They are organized as operons in which, usually, the antitoxin gene precedes the cognate toxin gene. The antitoxin generally acts as a transcriptional self-repressor, whereas the toxin acts as a co-repressor, both proteins constituting a harmless complex. When bacteria encounter a stressful environment, TAs are triggered. The antitoxin protein is unstable and will be degraded by host proteases, releasing the free toxin to halt essential processes. The result is a cessation of cell growth or even death. Because of their ubiquity and the essential processes targeted, TAs have been proposed as good candidates for development of novel antimicrobials. We discuss here the possible druggability of TAs as antivirals and antibacterials, with focus on the potentials and the challenges that their use may find in the ‘real’ world. We present strategies to develop TAs as antibacterials in view of novel technologies, such as the use of very small molecules (fragments) as inhibitors of protein–protein interactions. Appropriate fragments could disrupt the T:A interfaces leading to the release of the targeted TA pair. Possible ways of delivery and formulation of Tas are also discussed.

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“…MazF is used in the therapy of HIV and HCV [23, 25, 26]. The potential use of MazF in cancer was recently reported [27]. However, since both normal and tumor cells are sensitive to MazF, it is essential to develop specific and effective expression and delivery systems for MazF exclusively in tumor cells.…”

Section: Discussionmentioning

confidence: 99%

Selective eradication of cancer cells by delivery of adenovirus-based toxins

Shapira

Kazanov

et al. 2017

Oncotarget

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Background and objectiveKRAS mutation is an early event in colorectal cancer carcinogenesis. We previously reported that a recombinant adenovirus, carrying a pro-apoptotic gene (PUMA) under the regulation of Ets/AP1 (RAS-responsive elements) suppressed the growth of cancer cells harboring hyperactive KRAS. We propose to exploit the hyperactive RAS pathway, rather than to inhibit it as was previously tried and failed repeatedly. We aim to improve efficacy by substituting PUMA with a more potent toxin, the bacterial MazF-MazE toxin-antitoxin system, under a very tight regulation.ResultsA massive cell death, in a dose-dependent manner, reaching 73% at MOI 10 was seen in KRAS cells as compared to 22% in WT cells. Increase expression of MazE (the anti-toxin) protected normal cells from any possible internal or external leakage of the system and confirmed the selectivity, specificity and safety of the targeting system. Considerable tumor shrinkage (61%) was demonstrated in vivo following MazEF-encoding adenovirus treatment without any side effects.DesignEfficient vectors for cancer-directed gene delivery were constructed; “pAdEasy-Py4-SV40mP-mCherry-MazF”“pAdEasy-Py4-SV40mP-mCherry-MazF-IRES-TetR-CMVmp-MazE-IRES-EGFP“,“pAdEasy-ΔPy4-SV40mP-mCherry-MazF-IRES-TetR-CMVmp-MazE-IRES-EGFP “and “pAdEasy-mCherry”. Virus particles were produced and their potency was tested. Cell death was measured qualitatively by using the fluorescent microscopy and colony formation assay, and was quantified by MTT. FACS analysis using annexin V and RedDot2 dyes was performed for measuring apoptotic and dead cells, respectively. In vivo tumor formation was measured in a xenograft model.ConclusionsA proof of concept for a novel cancer safe and effective gene therapy exploiting an aberrant hyperactive pathway is achievable.

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Regression of Solid Tumors by Induction of MazF, a Bacterial mRNA Endoribonuclease

Cited by 13 publications

References 20 publications

Keeping the Wolves at Bay: Antitoxins of Prokaryotic Type II Toxin-Antitoxin Systems

Keeping the Wolves at Bay: Antitoxins of Prokaryotic Type II Toxin-Antitoxin Systems

One cannot rule them all: Are bacterial toxins-antitoxins druggable?

Selective eradication of cancer cells by delivery of adenovirus-based toxins

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