scholarly journals Proteasome inhibitor-induced modulation reveals the spliceosome as a specific therapeutic vulnerability in multiple myeloma

2018 ◽  
Author(s):  
Hector H. Huang ◽  
Ian D. Ferguson ◽  
Alexis M. Thornton ◽  
Christine Lam ◽  
Yu-Hsiu T. Lin ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Intron Retention ◽  
Proteasome Inhibitors ◽  
Protein Homeostasis ◽  
New Approach ◽  
Major Interest ◽  
Specific Alternative ◽  
Specific Vulnerability ◽  
Related Proteins ◽  
Anti Tumor Activity

AbstractEnhancing the efficacy of proteasome inhibitors is a central goal in myeloma therapy. We proposed that signaling-level responses after PI would reveal new mechanisms of action that could be therapeutically exploited. Unbiased phosphoproteomics after the PI carfilzomib surprisingly demonstrated the most prominent phosphorylation changes on splicing related proteins. Spliceosome modulation was invisible to RNA or protein abundance alone. Transcriptome analysis after PI demonstrated broad-scale intron retention, suggestive of spliceosome interference, as well as specific alternative splicing of protein homeostasis machinery components. These findings led us to evaluate direct spliceosome inhibition in myeloma, which synergized with carfilzomib and showed potent anti-tumor activity. Functional genomics and exome sequencing further supported the spliceosome as a specific vulnerability in myeloma. Our results propose splicing interference as an unrecognized modality of PI mechanism, reveal additional modes of spliceosome modulation, and suggest spliceosome targeting as a promising therapeutic strategy in myeloma.SignificanceNew ways to enhance PI efficacy are of major interest. We combine systems-level analyses to discover that PIs specifically interfere with splicing and that myeloma is selectively vulnerable to spliceosome inhibition. We reveal a new approach to advance myeloma therapy and uncover broader roles of splicing modulation in cancer.

scholarly journals Alantolactone inhibits cell autophagy and promotes apoptosis through targeting AP2M1 in acute lymphotic leukemia

2020 ◽  
Author(s):  
Ce Shi ◽  
Zhenkun Wang ◽  
Dongguang Yang ◽  
Jia Wei ◽  
Zhiyu Liu ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Acute Lymphoblastic Leukemia ◽  
Therapeutic Strategy ◽  
Molecular Mechanisms ◽  
Lymphoblastic Leukemia ◽  
Nude Mouse Model ◽  
Hematopoietic Malignancy ◽  
Different Types ◽  
Related Proteins ◽  
Anti Tumor Activity

Abstract Background: Acute lymphoblastic leukemia (ALL) is an aggressive hematopoietic malignancy and most commonly seen in children. Alantolactone (ATL) has been reported to have anti-tumor activities in different types of cancer. This study aimed to evaluate the anti-tumor activity and molecular mechanisms of ATL in ALL. Methods: The ALL cells were treated with 1, 5 and 10μM of of ALT, and then subjected to MTT assay and RNA sequencing. Flow cytometry, JC-1 staining and immunofluorescence staining assay were employed to measure cell apoptosis and autophagy. Meanwhile, western blot analysis was used to detect apoptosis and autophagy-related proteins. Finally, the effect of ALT on tumor growth was measured in BV173 xenograft nude mouse model. Results: In this study, we demonstrated that ALT could inhibit the proliferation of ALL cells by inducing apoptosis and inhibiting autophagy. Administration of rapamycin activated autophagy while reversing the effect of ALT on apoptosis. Mechanically, ALT could induce apoptosis and inhibit autophagy by promoting AM2P1 expression. Further, AM2P1 was figured to inhibit beclin1 phosphorylation so that the apartment between beclin1 and bcl-2 was alleviated to participate in the regulation of autophagy and apoptosis in ALL cell. Conclusions: This study disclosed that Alantolactone can inhibit cell autophagy and promote apoptosis through targeting AP2M1 in acute lymphotic leukemia, indicating a potential therapeutic strategy for ALLtreatment.

Inhibition of glioma by adenovirus KGHV500 encoding anti-p21Ras scFv and carried by cytokine-induced killer cells

2021 ◽  
pp. 153537022098676
Author(s):  
Jing Qian ◽  
Mo Yang ◽  
Qiang Feng ◽  
Xin-Yan Pan ◽  
Li-Lin Yang ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Glioma Cell ◽  
Therapeutic Strategy ◽  
Recombinant Adenovirus ◽  
Mapk Pathway ◽  
Control Treatment ◽  
Proliferation Index ◽  
Ras Gene ◽  
Cik Cells ◽  
Anti Tumor Activity

Ras gene mutation or overexpression can lead to tumorigenesis in multiple kinds of cancer, including glioma. However, no drugs targeting Ras or its expression products have been approved for clinical application thus far. Adenoviral gene therapy is a promising method for the treatment of glioma. In this study, the human glioma cell line U251 was co-cultured with recombinant adenovirus KGHV500, and the anti-tumor effects of KGHV500 were determined by MTT, scratch test, Transwell invasion, and apoptosis assays. Then, KGHV500 was delivered via the intravenous injection of CIK cells into glioma xenografts. Tumor volume, ki67 proliferation index, apoptosis levels, and anti-p21Ras scFv expression were tested to evaluate targeting ability, anti-tumor efficacy, and safety. We found that the KGHV500 exhibited anti-tumor activity in U251 cells and increased the intracellular expression of anti-p21Ras scFv compared with that in the control groups. CIK cells delivered KGHV500 to U251 glioma cell xenografts and enhanced anti-tumor activity against glioma xenografts compared to that produced by the control treatment. In conclusion, targeting Ras is a useful therapeutic strategy for gliomas and other Ras-driven cancers, and the delivery of anti-p21Ras scFv by recombinant adenovirus and CIK cells may play an essential role in the therapy of Ras-driven cancers. Impact statement For glioma treatment, gene therapy/virotherapy approach is a promising candidate. The Ras gene is reported to play a vital role in the RAS/RAF/mitogen-activated protein kinase (MAPK) pathway in gliomas. Thus, targeting the Ras gene should be a reasonable potential therapeutic method for glioma. In the present study, we used cytokine-induced killer (CIK) cells as secondary vectors to systemically deliver recombinant adenovirus KGHV500 to glioma xenografts and investigated the anti-tumor efficiency of recombinant adenovirus KGHV500 in vitro and in vivo. Our results expand evidence that targeting Ras is a useful and potential therapeutic strategy for gliomas. We believe that anti-p21Ras scFv delivered by recombinant adenovirus and CIK cells may play an important role in the therapy of Ras-driven cancers.

scholarly journals Hepatocyte-based flow analytical bioreactor for online xenobiotics metabolism bioprediction

2017 ◽  
Vol 4 ◽  
pp. 184954351770289
Author(s):  
M Helvenstein ◽  
S Hambÿe ◽  
B Blankert
Keyword(s):  
Iron Oxide ◽  
Iron Oxide Nanoparticles ◽  
High Performance ◽  
Screening Tools ◽  
Oxide Nanoparticles ◽  
New Approach ◽  
Drug Candidates ◽  
Magnetically Trapped ◽  
Major Interest

The research for new in vitro screening tools for predictive metabolic profiling of drug candidates is of major interest in the pharmaceutical field. The main motivation is to avoid late rejection in drug development and to deliver safer drugs to the market. Thanks to the superparamagnetic properties of iron oxide nanoparticles, a flow bioreactor has been developed which is able to perform xenobiotic metabolism studies. The selected cell line (HepaRG) maintained its metabolic competencies once iron oxide nanoparticles were internalized. Based on magnetically trapped cells in a homemade immobilization chamber, through which a flow of circulating phase was injected to transport nutrients and/or the studied xenobiotic, off-line and online (when coupled to a high-performance liquid chromatography chain) metabolic assays were developed using diclofenac as a reference compound. The diclofenac demonstrated a similar metabolization profile chromatogram, both with the newly developed setup and with the control situation. Highly versatile, this pioneering and innovative instrumental design paves the way for a new approach in predictive metabolism studies.

scholarly journals Chaperones and Proteostasis: Role in Parkinson’s Disease

Diseases ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 24 ◽  
Author(s):  
Neha Joshi ◽  
Atchaya Raveendran ◽  
Shirisha Nagotu
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Three Dimensional ◽  
Cellular Protein ◽  
The Body ◽  
Dimensional Structure ◽  
Protein Homeostasis ◽  
Altered Expression ◽  
And Function ◽  
Related Proteins

Proper folding to attain a defined three-dimensional structure is a prerequisite for the functionality of a protein. Improper folding that eventually leads to formation of protein aggregates is a hallmark of several neurodegenerative disorders. Loss of protein homeostasis triggered by cellular stress conditions is a major contributing factor for the formation of these toxic aggregates. A conserved class of proteins called chaperones and co-chaperones is implicated in maintaining the cellular protein homeostasis. Expanding the body of evidence highlights the role of chaperones as central mediators in the formation, de-aggregation and degradation of the aggregates. Altered expression and function of chaperones is associated with many neurodegenerative diseases including Parkinson’s disease. Several studies indicate that chaperones are at the center of the cause and effect cycle of this disease. An overview of the various chaperones that are associated with homeostasis of Parkinson’s disease-related proteins and their role in pathogenicity will be discussed in this review.

scholarly journals Multidimensional Proteomics Identifies Declines in Protein Homeostasis and Mitochondria as Early Signals for Normal Aging and Age-associated Disease in Drosophila

2019 ◽  
Vol 18 (10) ◽  
pp. 2078-2088 ◽  
Author(s):  
Lu Yang ◽  
Ye Cao ◽  
Jing Zhao ◽  
Yanshan Fang ◽  
Nan Liu ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Protein Dynamics ◽  
Isotope Labeling ◽  
Specific Protein ◽  
Normal Aging ◽  
Protein Homeostasis ◽  
Age Related ◽  
Muscle Tissues ◽  
Proteomic Study ◽  
Related Proteins

Aging is characterized by a gradual deterioration in proteome. However, how protein dynamics that changes with normal aging and in disease is less well understood. Here, we profiled the snapshots of aging proteome in Drosophila, from head and muscle tissues of post-mitotic somatic cells, and the testis of mitotically-active cells. Our data demonstrated that dysregulation of proteome homeostasis, or proteostasis, might be a common feature associated with age. We further used pulsed metabolic stable isotope labeling analysis to characterize protein synthesis. Interestingly, this study determined an age-modulated decline in protein synthesis with age, particularly in the pathways related to mitochondria, neurotransmission, and proteostasis. Importantly, this decline became dramatically accelerated in Pink1 mutants, a Drosophila model of human age-related Parkinson's disease. Taken together, our multidimensional proteomic study revealed tissue-specific protein dynamics with age, highlighting mitochondrial and proteostasis-related proteins. We suggest that declines in proteostasis and mitochondria early in life are critical signals prior to the onset of aging and aging-associated diseases.

scholarly journals Locked in a vicious cycle: the connection between genomic instability and a loss of protein homeostasis

2020 ◽  
Author(s):  
Wouter Huiting ◽  
Steven Bergink
Keyword(s):  
Control Systems ◽  
Genomic Instability ◽  
Therapeutic Strategy ◽  
Protein Quality ◽  
Accelerated Ageing ◽  
Protein Homeostasis ◽  
Vicious Cycle ◽  
Proteotoxic Stress ◽  
Gradual Loss ◽  
Wide Range

AbstractCardiomyopathies, neuropathies, cancer and accelerated ageing are unequivocally distinct diseases, yet they also show overlapping pathological hallmarks, including a gradual loss of genomic integrity and proteotoxic stress. Recent lines of evidence suggest that this overlap could be the result of remarkably interconnected molecular cascades between nuclear genomic instability and a loss of protein homeostasis. In this review, we discuss these complex connections, as well as their possible impact on disease. We focus in particular on the inherent ability of a wide range of genomic alterations to challenge protein homeostasis. In doing so, we provide evidence suggesting that a loss of protein homeostasis could be a far more prevalent consequence of genomic instability than generally believed. In certain cases, such as aneuploidy, a loss of protein homeostasis appears to be a crucial mechanism for pathology, which indicates that enhancing protein quality control systems could be a promising therapeutic strategy in diseases associated with genomic instability.

scholarly journals Sonodynamic and Photodynamics Used as a Combined Therapy in the Treatment of Malignant Neoplasms: Facts and Open Questions

2020 ◽  
Author(s):  
Heber Lopes de Mello ◽  
Luiz Anastacio Alves ◽  
Evellyn Araujo Dias ◽  
Sabrina de Sá Pereira Magalhães ◽  
Vinicius Cotta-de-Almeida ◽  
...  
Keyword(s):  
Cell Death ◽  
Combined Therapy ◽  
Low Frequency ◽  
Malignant Neoplasms ◽  
Tumor Treatment ◽  
New Approach ◽  
Common Path ◽  
Open Questions ◽  
Low Frequency Ultrasound ◽  
Anti Tumor Activity

Photodynamic therapy (PDT) used in combination with sonodynamic therapy (SDT) is a new approach that aims to increase the effectiveness of tumor treatment when compared to the effect of each independent therapy. PDT is based on stimulating sensitizers with photons, while the most accepted theory for SDT is that sensitizers are stimulated by the sonoluminescence phenomenon. However, after the excitation of the sensitizer, both therapies follow a common path, leading to the generation of free radicals and inducing cell death. One of the positive aspects of this combination is the augmentation of anti-tumor activity with fewer side effects, since cell death may be induced using lower sensitizer concentrations or less exposure to ultrasound or light. Another benefit of combining PDT and SDT, especially with the use of low-frequency ultrasound is the induction of sonophoresis. For instance, on the skin, it may facilitate the absorption of the sensitizer. However, research involving both PDT and SDT exhibit many variants, including differences in irradiation sources and their intensities, among others. These aspects contribute to a lack of standardization, leading to result variations, hindering assessment on the real contribution that these combined therapies can offer in tumor treatment. Thus, further research in the pre-clinical and clinical areas are crucial.

scholarly journals PADI2-mediated citrullination is required for efficient oligodendrocyte differentiation and myelination

2018 ◽  
Author(s):  
Ana Mendanha Falcão ◽  
Mandy Meijer ◽  
Antonella Scaglione ◽  
Puneet Rinwa ◽  
Eneritz Agirre ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Corpus Callosum ◽  
Therapeutic Strategy ◽  
Chromatin Accessibility ◽  
Motor Dysfunction ◽  
Peptidylarginine Deiminase ◽  
Oligodendrocyte Differentiation ◽  
Associated Proteins ◽  
Arginine Residues ◽  
Related Proteins

Citrullination, the deimination of arginine residues into citrulline, has been implicated in the aetiology of several diseases. In multiple sclerosis (MS), citrullination is thought to be a major driver of pathology, through hypercitrullination and destabilization of myelin. As such, inhibition of citrullination has been suggested as a therapeutic strategy for MS. Here, in contrast, we show citrullination by peptidylarginine deiminase 2 (PADI2) is required for normal oligodendrocyte differentiation, myelination and motor function. We identify several targets for PADI2, including myelin-related proteins and chromatin-associated proteins, implicating PADI2 in epigenetic regulation. Accordingly, we observe that PADI2 inhibition and its knockdown affect chromatin accessibility and prevent the upregulation of oligodendrocyte differentiation genes. Moreover, mice lacking PADI2, display motor dysfunction and decreased number of myelinated axons in the corpus callosum. We conclude that citrullination is required for oligodendrocyte lineage progression and myelination and suggest its targeted activation in the oligodendrocyte lineage might be beneficial in the context of remyelination.

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