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Cell May 2022Cancer cells are featured with uncontrollable activation of cell cycle, and microRNA deficiency drives tumorigenesis. The RNA-dependent RNA polymerase (RDR) is essential...
Cancer cells are featured with uncontrollable activation of cell cycle, and microRNA deficiency drives tumorigenesis. The RNA-dependent RNA polymerase (RDR) is essential for small-RNA-mediated immune response in plants but is absent in vertebrates. Here, we show that ectopic expression of plant RDR1 can generally inhibit cancer cell proliferation. In many human primary tumors, abnormal microRNA isoforms with 1-nt-shorter 3' ends are widely accumulated. RDR1 with nucleotidyltransferase activity can recognize and modify the problematic AGO2-free microRNA duplexes with mononucleotides to restore their 2 nt overhang structure, which eventually rescues AGO2-loading efficiency and elevates global miRNA expression to inhibit cancer cell-cycle specifically. The broad antitumor effects of RDR1, which can be delivered by an adeno-associated virus, are visualized in multiple xenograft tumor models in vivo. Altogether, we reveal the widespread accumulation of aberrant microRNA isoforms in tumors and develop a plant RDR1-mediated antitumor stratagem by editing and repairing defective microRNAs.
Topics: Animals; Humans; Immunity; MicroRNAs; Plant Proteins; Plants; RNA-Dependent RNA Polymerase
PubMed: 35623329
DOI: 10.1016/j.cell.2022.04.030 -
EcoSal Plus Dec 2022In the late 1950s, a number of laboratories took up the study of plasmids once the discovery was made that extrachromosomal antibiotic resistance (R) factors are the... (Review)
Review
In the late 1950s, a number of laboratories took up the study of plasmids once the discovery was made that extrachromosomal antibiotic resistance (R) factors are the responsible agents for the transmissibility of multiple antibiotic resistance among the enterobacteria. The use of incompatibility for the classification of plasmids is now widespread. It seems clear now on the basis of the limited studies to date that the number of incompatibility groups of plasmids will likely be extremely large when one includes plasmids obtained from bacteria that are normal inhabitants of poorly studied natural environments. The presence of both linear chromosomes and linear plasmids is now established for several species. One of the more fascinating developments in plasmid biology was the discovery of linear plasmids in the 1980s. A remarkable feature of the Ti plasmids of Agrobacterium tumefaciens is the presence of two DNA transfer systems. A definitive demonstration that plasmids consisted of duplex DNA came from interspecies conjugal transfer of plasmids followed by separation of plasmid DNA from chromosomal DNA by equilibrium buoyant density centrifugation. The formation of channels for DNA movement and the actual steps involved in DNA transport offer many opportunities for the discovery of proteins with novel activities and for establishing fundamentally new concepts of macromolecular interactions between DNA and specific proteins, membranes, and the peptidoglycan matrix.
Topics: Plasmids; Agrobacterium tumefaciens; Plant Tumor-Inducing Plasmids; Bacteria; DNA, Bacterial
PubMed: 35373578
DOI: 10.1128/ecosalplus.esp-0028-2021 -
Current Opinion in Biotechnology Feb 2020Plants are routinely utilized as efficient production platforms for the development of anti-cancer biologics leading to novel anti-cancer vaccines, immunotherapies, and... (Review)
Review
Plants are routinely utilized as efficient production platforms for the development of anti-cancer biologics leading to novel anti-cancer vaccines, immunotherapies, and drug-delivery modalities. Various biosimilar/biobetter antibodies and immunogens based on tumor-associated antigens have been produced and optimized for plant expression. Plant virus nanoparticles, including those derived from cowpea mosaic virus or tobacco mosaic virus in particular have shown promise as immunotherapies stimulating tumor-associated immune cells and as drug carriers delivering conjugated chemotherapeutics effectively to tumors. Advancements have also been made toward the development of lectins that can selectively recognize cancer cells. The ease at which plant systems can be utilized for the production of these products presents an opportunity to further develop novel and exciting anti-cancer biologics.
Topics: Biological Products; Cancer Vaccines; Comovirus; Drug Carriers; Tobacco Mosaic Virus
PubMed: 31785553
DOI: 10.1016/j.copbio.2019.11.004 -
Journal of Nanobiotechnology Jan 2023While several artificial nanodrugs have been approved for clinical treatment of breast tumor, their long-term applications are restricted by unsatisfactory therapeutic...
While several artificial nanodrugs have been approved for clinical treatment of breast tumor, their long-term applications are restricted by unsatisfactory therapeutic outcomes, side reactions and high costs. Conversely, edible plant-derived natural nanotherapeutics (NTs) are source-widespread and cost-effective, which have been shown remarkably effective in disease treatment. Herein, we extracted and purified exosome-like NTs from tea leaves (TLNTs), which had an average diameter of 166.9 nm and a negative-charged surface of - 28.8 mV. These TLNTs contained an adequate slew of functional components such as lipids, proteins and pharmacologically active molecules. In vitro studies indicated that TLNTs were effectively internalized by breast tumor cells (4T1 cells) and caused a 2.5-fold increase in the amount of intracellular reactive oxygen species (ROS) after incubation for 8 h. The high levels of ROS triggered mitochondrial damages and arrested cell cycles, resulting in the apoptosis of tumor cells. The mouse experiments revealed that TLNTs achieved good therapeutic effects against breast tumors regardless of intravenous injection and oral administration through direct pro-apoptosis and microbiota modulation. Strikingly, the intravenous injection of TLNTs, not oral administration, yielded obvious hepatorenal toxicity and immune activation. These findings collectively demonstrate that TLNTs can be developed as a promising oral therapeutic platform for the treatment of breast cancer.
Topics: Animals; Mice; Exosomes; Reactive Oxygen Species; Mammary Neoplasms, Animal; Apoptosis; Microbiota; Plant Leaves; Tea; Cell Line, Tumor
PubMed: 36600299
DOI: 10.1186/s12951-022-01755-5 -
Microbiology Spectrum Dec 2014Agrobacterium tumefaciens is a plant pathogen with the capacity to deliver a segment of oncogenic DNA carried on a large plasmid called the tumor-inducing or Ti plasmid... (Review)
Review
Agrobacterium tumefaciens is a plant pathogen with the capacity to deliver a segment of oncogenic DNA carried on a large plasmid called the tumor-inducing or Ti plasmid to susceptible plant cells. A. tumefaciens belongs to the class Alphaproteobacteria, whose members include other plant pathogens (Agrobacterium rhizogenes), plant and insect symbionts (Rhizobium spp. and Wolbachia spp., respectively), human pathogens (Brucella spp., Bartonella spp., Rickettsia spp.), and nonpathogens (Caulobacter crescentus, Rhodobacter sphaeroides). Many species of Alphaproteobacteria carry large plasmids ranging in size from ∼100 kb to nearly 2 Mb. These large replicons typically code for functions essential for cell physiology, pathogenesis, or symbiosis. Most of these elements rely on a conserved gene cassette termed repABC for replication and partitioning, and maintenance at only one or a few copies per cell. The subject of this review is the ∼200-kb Ti plasmids carried by infectious strains of A. tumefaciens. We will summarize the features of this plasmid as a representative of the repABC family of megaplasmids. We will also describe novel features of this plasmid that enable A. tumefaciens cells to incite tumor formation in plants, sense and respond to an array of plant host and bacterial signal molecules, and maintain and disseminate the plasmid among populations of agrobacteria. At the end of this review, we will describe how this natural genetic engineer has been adapted to spawn an entire industry of plant biotechnology and review its potential for use in future therapeutic applications of plant and nonplant species.
Topics: Agrobacterium tumefaciens; DNA Replication; DNA, Bacterial; Plant Diseases; Plant Tumor-Inducing Plasmids; Plants
PubMed: 25593788
DOI: 10.1128/microbiolspec.PLAS-0010-2013 -
Molecules (Basel, Switzerland) Apr 2015The sesquiterpene lactone thapsigargin is found in the plant Thapsia garganica L., and is one of the major constituents of the roots and fruits of this Mediterranean... (Review)
Review
The sesquiterpene lactone thapsigargin is found in the plant Thapsia garganica L., and is one of the major constituents of the roots and fruits of this Mediterranean species. In 1978, the first pharmacological effects of thapsigargin were established and the full structure was elucidated in 1985. Shortly after, the overall mechanism of the Sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) inhibition that leads to apoptosis was discovered. Thapsigargin has a potent antagonistic effect on the SERCA and is widely used to study Ca2+-signaling. The effect on SERCA has also been utilized in the treatment of solid tumors. A prodrug has been designed to target the blood vessels of cancer cells; the death of these blood vessels then leads to tumor necrosis. The first clinical trials of this drug were initiated in 2008, and the potent drug is expected to enter the market in the near future under the generic name Mipsagargin (G-202). This review will describe the discovery of the new drug, the on-going elucidation of the biosynthesis of thapsigargin in the plant and attempts to supply the global market with a novel potent anti-cancer drug.
Topics: Fermentation; Thapsia; Thapsigargin
PubMed: 25856061
DOI: 10.3390/molecules20046113 -
Vaccines Aug 2022Breast cancer treatment using plant-virus-based nanoparticles (PVNPs) has achieved considerable success in preclinical studies. PVNP-based breast cancer therapies... (Review)
Review
Breast cancer treatment using plant-virus-based nanoparticles (PVNPs) has achieved considerable success in preclinical studies. PVNP-based breast cancer therapies include non-targeted and targeted nanoplatforms for delivery of anticancer therapeutic chemo and immune agents and cancer vaccines for activation of local and systemic antitumor immunity. Interestingly, PVNP platforms combined with other tumor immunotherapeutic options and other modalities of oncotherapy can improve tumor efficacy treatment. These applications can be achieved by encapsulation of a wide range of active ingredients and conjugating ligands for targeting immune and tumor cells. This review presents the current breast cancer treatments based on PVNP platforms.
PubMed: 36146510
DOI: 10.3390/vaccines10091431 -
International Journal of Ophthalmology 2022Retinoblastoma (RB) is a highly aggressive ocular tumor, and due to socioeconomic and medical constraints, many children receive treatment only in the metaphase and... (Review)
Review
Retinoblastoma (RB) is a highly aggressive ocular tumor, and due to socioeconomic and medical constraints, many children receive treatment only in the metaphase and advanced clinical stages, resulting in high rates of blindness and disability. Although several approaches exist in the treatment of RB, some children with the disease do not have satisfactory results because of various factors. Plant-derived natural products have shown definite therapeutic effects in the treatment of various tumors and are also widely used in the study of RB. We review plant-derived natural products used in the study of anti-RB to provide ideas for the clinical application of these drugs and the development of new therapeutic drugs.
PubMed: 36017045
DOI: 10.18240/ijo.2022.08.24 -
Translational Oncology Jan 2021Recent studies in microbial pathogenesis have identified several bacterial proteins with the potential to influence host cell nuclei. This field of research is in its... (Review)
Review
Recent studies in microbial pathogenesis have identified several bacterial proteins with the potential to influence host cell nuclei. This field of research is in its infancy, however it is rapidly growing. In particular, the role of bacterial nucleomodulins in animal oncogenesis is an area that requires attention. Earlier research has suggested the role of nucleomodulins in plant tumor development and these findings may provide us with a better understanding of the role of these proteins in human cancer development. This proposition is further supported by previous identification of nucleomodulins present in bacteria that have been associated with cancer development, but their role in human cancer is unclear. In this article, we provide an update on the status of these nucleomodulins and their role in cancer etiology. We collected information about known bacterial nucleomodulins and tried to relate their mechanistic implication with already known plant tumor development model. The present research indicates that bacterial nucleomodulins may be an important target in cancer etiology and knowledge of their role in human oncogenesis may help us to create suitable alternative cancer management strategies.
PubMed: 33137543
DOI: 10.1016/j.tranon.2020.100922 -
Cell & Bioscience Oct 2021In modern research, mitochondria are considered a more crucial energy plant in cells. Mitochondrial dysfunction, including mitochondrial DNA (mtDNA) mutation and... (Review)
Review
In modern research, mitochondria are considered a more crucial energy plant in cells. Mitochondrial dysfunction, including mitochondrial DNA (mtDNA) mutation and denatured protein accumulation, is a common feature of tumors. The dysfunctional mitochondria reprogram molecular metabolism and allow tumor cells to proliferate in the hostile microenvironment. One of the crucial signaling pathways of the mitochondrial dysfunction activation in the tumor cells is the retrograde signaling of mitochondria-nucleus interaction, mitochondrial unfolded protein response (UPR), which is initiated by accumulation of denatured protein and excess ROS production. In the process of UPR, various components are activitated to enhance the mitochondria-nucleus retrograde signaling to promote carcinoma progression, including hypoxia-inducible factor (HIF), activating transcription factor ATF-4, ATF-5, CHOP, AKT, AMPK. The retrograde signaling molecules of overexpression ATF-5, SIRT3, CREB, SOD1, SOD2, early growth response protein 1 (EGR1), ATF2, CCAAT/enhancer-binding protein-d, and CHOP also involved in the process. Targeted blockage of the UPR pathway could obviously inhibit tumor proliferation and metastasis. This review indicates the UPR pathways and its crucial role in targeted therapy of metastasis tumors.
PubMed: 34717757
DOI: 10.1186/s13578-021-00696-0