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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 1,747 records · Page 97
All sourcesNASA NTRSDOE OSTI
DOE OSTI2018

Comparative characterization of stem cells from human exfoliated deciduous teeth, dental pulp, and bone marrow–derived mesenchymal stem cells

Highlights: • We compared the in vitro characteristics of dental pulp stem cells from deciduous teeth (SHED), human dental pulp stem cells (hDPSCs), and human bone marrow mesenchymal stem cells (hBMSCs). • SHED exhibit greater proliferative potential than hDPSCs and hBMSCs. • SHED exhibited higher proliferative activity and levels of bFGF and BMP-2 gene expression compared with BMMSCs and DPSCs. The ease of harvesting cells and ability to avoid invasive surgical procedures suggest that SHED may be a useful cell source for application in bone regeneration treatments. Mesenchymal stem cells (MSCs) are used clinically in tissue engineering and regenerative medicine. The proliferation and osteogenic differentiation potential of MSCs vary according to factors such as tissue source and cell population heterogeneity. Dental tissue has received attention as an easily accessible source of high-quality stem cells. In this study, we compared the in vitro characteristics of dental pulp stem cells from deciduous teeth (SHED), human dental pulp stem cells (hDPSCs), and human bone marrow mesenchymal stem cells (hBMSCs).

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Proteasome-mediated protein degradation is enhanced by fusion ubiquitin with unstructured degron

Highlights: • We constructed a fusion protein comprising ubiquitin and Rpn4-derived unstructured region. • The fusion ubiquitin retained its function of polyubiquitination of target proteins. • The fusion ubiquitin induced more efficient proteasomal target degradation than wild-type ubiquitin. Methods to induce proteasomal degradation of unwanted proteins are valuable in biomedical studies and thus receive increasing attention. For efficient degradation, the proteasome requires both a ubiquitin tag, which delivers substrates to the proteasome, and an unstructured region, where the proteasome engages the substrate for unfolding and degradation. We fused two degron components into a single molecule to create a fusion protein comprising ubiquitin and Rpn4-derived unstructured region. We demonstrated that the fusion protein retained its function to polyubiquitinate target proteins, thereby inducing more efficient proteasomal target degradation than wild-type ubiquitin in vitro and in cells. These results provide novel strategies for robust degradation enhancement of polyubiquitinated proteins.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Revisit the effect of fibrillization on functions of prion protein from the perspective of Cu(II) binding

Conversion of prion protein (PrP) from its α-helical form to a β-sheet rich scrapie form constitutes the key event of the etiology of prion diseases. Fundamental questions remain concerning the functions of prion protein and the mechanisms leading to the formation of misfolded forms. }A wealth of evidence links physiological functions of PrP to its ability to bind Cu(II), suggesting that it may act as a copper buffer or be part of the copper transportation system. In contrast, much less attention has been devoted to understanding Cu(II) binding to the scrapie forms. The goal of this work is to comparatively investigate the coordination geometries among PrP conformers at different pH values using continuous X-band electron paramagnetic resonance (EPR) spectroscopy. We have found that while both α-helical monomeric and fibrillar forms of PrP bind Cu(II) similarly, the multi-His configuration is more favored in the fibrillar form. Our results have provided insights into the effect of fibrillization on the functions of prion protein.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

SIRT1 promotes proliferation, migration, and invasion of breast cancer cell line MCF-7 by upregulating DNA polymerase delta1 (POLD1)

Highlights: • SIRT1 is increased in clinical breast cancer tissues. • SIRT1 is upregulated in breast cancer cell line MCF-7. • SIRT1 and p125 are positively correlated in clinical breast cancer tissues. • SIRT1 can upregulate the expression level of POLD1/p125 in MCF-7 cells. Sirtuin 1 (SIRT1), class III histone deacetylase, plays an important character in cell proliferation, cell cycle, apoptosis, energy metabolism and DNA repair. In recent years, researchers have attached increasing attention on the role of SIRT1 in tumorigenesis, development and drug resistance. The effect of SIRT1 on breast cancer is still controversial and its exact role remains to be elucidated. In the present study, we investigated the significant role of SIRT1 in breast cancer by exploring the effect of SIRT1 on DNA polymerase delta1 (POLD1), the gene coding for DNA polymerase δ catalytic subunit p125. Immunohistochemistry showed that the protein expression level of SIRT1 was higher in breast cancer tissues relative to adjacent normal tissues. Knockdown of SIRT1 by shRNA decreased the proliferation, migration, and invasion of human breast cancer cell line MCF-7, while the overexpression of SIRT1 promoted the proliferation, migration, and invasion of MCF-7 cells. Clinically, the immunohistochemistry results revealed that the expression of SIRT1 was positively correlated with p125. Further analysis demonstrated that silencing of SIRT1 increased the expression of p53, while the expression level of POLD1/p125 decreased, and the result by overexpressing SIRT1 was opposite. Collectively, these data suggest that SIRT1 is an oncogenic factor in breast cancer cells and can be involved in the progression of breast cancer by inhibiting p53 and activating POLD1. Our finding provides new insights into the mechanisms of breast cancer.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Shelterin differentially respond to oxidative stress induced by TiO2-NPs and regulate telomere length in human hepatocytes and hepatocarcinoma cells in vitro

Highlights: • Exposed to TiO{sub 2}-NPs caused telomere shortening and chromosome instability in normal cells but not in cancer cells. • The shelterin and Nrf-2 of normal and cancer cells differentially respond to oxidative stress induced by TiO{sub 2}-NPs. • The upregulation of Nrf-2 and shelterin protect telomere and chromosome stability against TiO{sub 2}-NPs exposure. Titanium dioxide nanoparticles (TiO{sub 2}-NPs) have raised serious attention for their widely use and potential adverse effects on human mainly due to producing ROS. However, the influence of TiO{sub 2}-NPs on telomere maintaining has not been studied clearly. Shelterin plays core roles in telomere length (TL) regulation. Abnormal TL are associated with chromosome instability (CIN) and high risk of diseases. This study investigated whether TiO{sub 2}-NPs affect TL to induce CIN through ROS generation and the possible mechanisms. Human hepatocyte L-02 and hepatocarcinoma cells QGY were exposed to TiO{sub 2}-NPs (0, 40, 80 μg/mL) for 72 h. The intracellular hydrogen dioxide (H{sub 2}O{sub 2}) concentration were measured. The TL, Nrf-2, and three core shelterin components (TRF1, TRF2, and POT1) transcription level were determined by quantitative real-time PCR. CIN was measured by cytokinesis-block micronucleus assay. TiO{sub 2}-NPs exposure increased intracellular H{sub 2}O{sub 2} in both L-02 and QGY cells, and induced Nrf-2, TRF1, TRF2, POT1 downregulated transcription compared with control (P P P P Nrf-2 to oxidative stress induced by TiO{sub 2}-NPs led to the weakened telomere protection in normal cells and effective telomere maintenance in cancer cells, respectively. The upregulation of Nrf-2 and shelterin could protect TL and chromosome stability against TiO{sub 2}-NPs exposure.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Unfolding of IgG domains detected by non-reducing SDS-PAGE

Highlights: • Aberrant artefactual mAb masses and size heterogeneity noted by non-reducing SDS-PAGE. • This effect depends on pre-electrophoresis sample heating temperatures and conditions. • These phenomena are also observed for a commercial human IgG{sub 1} polyclonal antibody. • Multiple observed bands hypothesized to reflect IgG domain thermal unfolding in SDS. • These results are likely relevant to analyses of many monoclonal and polyclonal Abs. Monoclonal antibodies are very important in modern therapeutics and constitute a substantial percentage of newly approved drugs. Every therapeutic monoclonal antibody must be analyzed for structural and functional integrity, and all protein heterogeneities need to be identified and quantified. The conformational stabilities of the monoclonal antibodies are also important for antibody storage and handling stabilities. One of the first and simplest of the structural analysis techniques utilized is SDS-PAGE, which can be performed both with and without prior reduction to break disulfide bonds. This permits sizing of both heavy and light chains in the reduced condition, and sizing of the intact antibody and any disulfide aggregates in the non-reduced condition. Analyzing our human anti-cocaine monoclonal antibody, we noted unexpectedly larger apparent molecular weights and apparent protein size heterogeneities using non-reducing SDS-PAGE. These apparent molecular weight heterogeneities are not consistent with other analysis techniques. Heterogeneities were noted using several heating and pre-electrophoretic sample preparation protocols, and are modified by the inclusion of small concentrations of certain alcohols such as propanol and butanol. All of these unexpected results were also observed for a commercial human IgG{sub 1} antibody, suggesting that these observations are applicable to IgGs in general. Thus, careful attention must be paid to the interpretation of non-reducing SDS-PAGE results for IgGs. It is hypothesized that differential thermal unfolding of the Fab, CH2 and CH3 domains of the IgGs in SDS give rise to the stable, discrete bands observed using different heating protocols prior to non-reducing SDS-PAGE.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Upregulation of lncRNA VDR/CASC15 induced by facilitates cardiac hypertrophy through modulating miR-432-5p/TLR4 axis

Sustained cardiac hypertrophy has threatened human health. With the development of human genome project, non-coding RNAs (ncRNAs) have attracted more and more attentions of researchers. As a subgroup of ncRNAs, long non-coding RNAs (lncRNAs) has been widely studied in human diseases, including cardiac hypertrophy. According to search results of bioinformatics website, lncRNA CASC15 potentially participates in the course of cardiac hypertrophy. According to the result of qRT-PCR, CASC15 expression was upregulated when cardiomyocytes were treated with Ang-II. Moreover, CASC15 was highly expressed in cardiac hypertrophic model. Upregulation of CASC15 was accompanied with some hypertrophic responses. To explore the specific biological function of CASC15 in cardiac hypertrophy, loss-of-function experiments were conducted in Ang-II-induced cardiomyocytes. Results of immunofluorence staining revealed that cell surface area enlarged by Ang-II was decreased when CASC15 was silenced. The expression levels of hypertrophic factors were attenuated by knockdown of CASC15. To detect the molecular mechanism by which CASC15 regulates the progression of cardiac hypertrophy, mechanism experiments were designed and carried out. It was found that CASC15 was activated by the transcription factor VDR. Furthermore, CASC15 can upregulate TLR4 by competitively binding miR-432-5p. In conclusion, Upregulation of lncRNA CASC15 induced by VDR facilitates cardiac hypertrophy via miR-432-5p/TLR4 axis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

CircRNA circ-BANP-mediated miR-503/LARP1 signaling contributes to lung cancer progression

Recently, circular RNAs (circRNAs) attract much attention due to their potential vital functions in multiple human diseases, including cancer. circ-BANP has been reported to modulate colorectal cancer growth. Nevertheless, the relationship between circ-BANP and lung cancer requires to be investigated. In this study, we found circ-BANP was overexpressed in lung cancer tissues. Higher circ-BANP expression was associated with lower survival rate. Moreover, silencing circ-BANP markedly inhibited proliferation, migration and invasion of lung cancer cells in vitro and impaired tumor propagation in vivo. In mechanism, circ-BANP was identified as the sponge of miR-503 while miR-503 targets LARP1. Circ-BANP-induced inhibition of miR-503 led to increased expression of LARP1 in lung cancer. Finally, rescue assays indicated that LARP1 restoration partially reversed the effects of circ-BANP knockdown in lung cancer. In sum, our study illustrated that circ-BANP-mediated miR-503/LARP1 signaling promoted lung cancer growth, migration and invasion, providing a novel insight on the mechanism underlying lung cancer progression.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

miR-410–3p promotes prostate cancer progression via regulating PTEN/AKT/mTOR signaling pathway

Prostate cancer has become one of commonest urologic tumors in male. In recent years, miRNAs are continually attracting attentions of researchers for their special regulatory function in human cancers. Previous study has revealed that miR-410 acts as a biomarker for the diagnosis of prostate cancer. Whereas, the specific biological function of miR-410–3p in prostate cancer remains unknown. The aim of this study is to explore the function and molecular mechanism of miR-410–3p in prostate cancer. The high expression of miR-410–3p was examined in prostate cancer tissues and cell lines by qRT-PCR. Next, the prognostic value was identified by Kaplan Meier method. High expression of miR-410–3p indicated poor prognosis of prostate cancer patients. To investigate the biological function of miR-410–3p in prostate cancer, loss-of function assays were designed and performed in two prostate cancer cell lines (PC3 and DU145). As a result, downregulated miR-410–3p suppressed cell proliferation, migration and EMT progress. Moreover, flow cytometry analysis was performed to determine that the acceleration effects of miR-410–3p on cell apoptosis. Mechanistically, further analysis demonstrated that the effects of miR-410–3p exert oncogenic functions through downregulating PTEN. All findings in this study revealed that miR-410–3p inhibits prostate cancer progression via downregulating PTEN/AKT/mTOR signaling pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Auriculasin from Flemingia philippinensis roots shows good therapeutic indexes on hyperactive behavior in zebrafish

Highlights: • Auriculasin regulates dopamine secretion through per1b. • Auriculasin shows good therapeutic indexes on hyperactive behavior in zebrafish. • Auriculasin have potential therapeutic indexes on ADHD. Previously, period1b−/− zebrafish mutants were used to establish an attention deficit hyperactivity disorder (ADHD) model, in which hyperactive behavior was found to be a typical characteristic of ADHD due to down-regulated dopamine levels. Here, we used five prenylated isoflavones from Flemingia philippinensis roots to study their therapeutic effects on hyperactivity behavior in period1b−/− zebrafish. Results of locomotor activity assay showed that auriculasin, one of the prenylated isoflavones, significantly reduced the hyperactivity behavior in period1b−/− zebrafish. Hormone measurement results showed that auriculasin increased melatonin and dopamine content. Results of quantitative real-time polymerase chain reaction showed that auriculasin down-regulated the expression of mao but up-regulated the expression of th and per1b. Thus, auriculasin demonstrated a potential biological effect on dopamine activity to inhibit hyperactivity behavior in the ADHD zebrafish model by regulating circadian clock gene per1b.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Ketohexokinase is involved in fructose utilization and promotes tumor progression in glioma

Highlights: • KHK was overexpressed in glioma and correlated with glioma malignancy and patients' poor survival. • Silencing KHK could significantly inhibit glioma cell proliferation and migration in fructose medium. • Culturing glioma cells in fructose medium could promote the expression of KHK and increase cells malignancy progression. Many studies have pinpointed that fructose could be utilized as a carbon source in some cancers, and we also defined that glioma cells could utilize fructose to maintain themselves survival and proliferation depending on GLUT5 expression recently. However, ketohexokinase (KHK), as a key enzyme involved in fructose catabolism, drew less attention in cancers, especially in glioma. In the present study, we first analyzed the expression levels of KHK in glioma tissues and the correlations of KHK expression with clinicopathological variables of patients with glioma. Meanwhile, we detected the effect of silencing KHK on the biological functions of glioma cells in fructose medium. From the results, we found that KHK was expressed at significantly higher level in glioma tissues than in non-tumor brain, and KHK expression was significantly correlated with tumor malignancy and poor survival of glioma patients (p < 0.01). Functionally, knockdown of KHK could significantly inhibit cell proliferation and migration of glioma cells in fructose medium. Furthermore, we investigated the KHK expression level after long-time treatment with fructose, and detected the change of cell biological behaviour, then we found that the expression level of KHK was significantly increased and these cells showed more malignant properties. Taken together, our results suggest that high fructose diet and KHK overexpression are correlated with glioma malignant progression and patients' poor survival, and we believe this hypothesis would open the door for novel therapeutic agents and mentalities for glioma.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

LncRNA LINC00641 predicts prognosis and inhibits bladder cancer progression through miR-197-3p/KLF10/PTEN/PI3K/AKT cascade

As a new group of important effector molecules involved in multiple cancers, long noncoding RNAs (lncRNAs) have attracted much attention recently. Especially, evidences have indicated lncRNAs might be promising biomarkers and targets for cancer therapy. LINC00641 is a novel lncRNA, whose function remains totally unclear. The aim of our study was to determine the functions of LINC00641 in bladder cancer. We found that LINC00641 expression was significantly down-regulated in bladder cancer tissues. Down-regulation of LINC00641 in patients with bladder cancer predicts poor prognosis. Gain-of-function assays indicated that LINC00641 up-regulation markedly inhibited the proliferation, migration and invasion of bladder cancer cells. Xenograft assay also confirmed that LINC00641 overexpression suppressed bladder cancer growth in vivo. Mechanistically, LINC00641 was demonstrated to interact with miR-197-3p, whose target was KLF10. By up-regulating KLF10 level, LINC00641 suppressed the PTEN/PI3K/AKT pathway, leading to prevention of bladder cancer progression. Taken together, our study illustrated a novel signaling cascade of LINC00641/miR-197-3p/KLF10/PTEN/PI3K/AKT pathway regulating bladder cancer development.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

LncRNA HAND2-AS1 sponging miR-1275 suppresses colorectal cancer progression by upregulating KLF14

Long noncoding RNAs (lncRNAs) represent a novel type of noncoding RNAs of over 200 nucleotides, characterized by no or limited protein-coding potential. Although the function of lncRNAs attracts increasing attention recently, the relationship between lncRNA and colorectal cancer (CRC) remains further investigation. In our study, we found that lncRNA HAND2-AS1 was markedly downregulated in CRC tissues. And its expression level was negatively correlated with metastasis and advanced stage in CRC patients. Furthermore, we showed that HAND2-AS1 low expression predicted poor prognosis. Functionally, we found that overexpression of HAND2-AS1 obviously attenuated the proliferation and invasion of CRC cells. Ectopic expression of HAND2-AS1 also inhibited tumor propagation in vivo. In mechanism, HAND2-AS1 served as a sponge of miR-1275 which targeted KLF14. Through facilitating KLF14 expression, HAND2-AS1 suppressed CRC progression. In conclusion, our study demonstrated that HAND2-AS1 exerts a suppressive role in CRC by sponging miR-1275 and modulating KLF14 expression.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Gliadin intake induces oxidative-stress responses in Caenorhabditis elegans

Highlights: • Locomotion behavior and brood size were reduced in C. elegans fed with gliadin. • ROS production and oxidative-stress responses were increased with gliadin intake. • Reduction in pumping rate was caused by the gliadin-induced oxidative stress. Clinical attention to gluten-related disorders, such as celiac disease and nonceliac gluten sensitivity, is on the rise. However, identifying the pathophysiological mechanisms of gluten-related disorders remains elusive. Gliadin, a component of gluten, is known to play a major role in gluten toxicity. Caenorhabditis elegans has been widely used as the predominant experimental animal model to study toxicity and stress response in biomedical research. We investigated the stress response induced by gliadin intake in C. elegans to evaluate its toxicity and found brood size, body bending, and pumping rates to be significantly altered in response to gliadin. Notably, reactive oxygen species (ROS) production and Pgst-4::GFP transgene expression, an indicator of the oxidative-stress response, were significantly increased after gliadin intake. Reduced pumping rates were most likely caused by gliadin-induced oxidative stress, since pumping rates in oxidative stress-sensitive mev-1 mutants were more severely reduced than in oxidative stress-resistant daf-2 mutants following gliadin intake. Our results indicated that gluten/gliadin intake in C. elegans triggered ROS production and induced an oxidative stress response that reduced pumping rates and decreased brood size. We suggest C. elegans to be a useful model system for studying gluten/gliadin toxicity.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Linkage between lipid droplet formation and nuclear deformation in HeLa human cervical cancer cells

Highlights: • Oleic acid (OA) induces cytoplasmic, but not nucleoplasmic, LDs in HeLa cells. • Cells harboring OA-induced cytoplasmic LDs exhibit deformity of the nucleus. • Multinucleation by paclitaxel and reversine treatment coincides with LD formation. • LD formation and nuclear deformation are mutually affectable. Because lipid droplets (LDs) and the nucleus are cellular organelles that regulate seemingly very different biochemical processes, very little attention has been focused on their possible interplay. Here, we report a correlation between nuclear morphology and cytoplasmic LD formation in HeLa human cervical cells. When the cells were treated with oleic acid (OA), LDs were formed in the cytoplasm, but not in the nucleoplasm. Interestingly, cells harboring OA-induced cytoplasmic LDs showed deformity of the nucleus, particularly at the nuclear rim. Conversely, when alteration from a single spherical nuclear shape to a multinucleated form was enforced by coadministration of paclitaxel and reversine, a significant amount of LDs was detected in the cytoplasm of the multinucleated cells. These two distinct pharmacological culture conditions not only allow analysis of the previously underappreciated organelle relationship, but also provide insights into the mutual affectability of LD formation and nuclear deformation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Graphene-based materials: The missing piece in nanomedicine?

Nanomedicine utilizes biocompatible nanomaterials for therapeutic as well as imaging purposes for the treatment of various diseases including cancer, neurological disorders and wound infections. Graphene and its modified nanostructures have attracted much attention in recent years in nanomedicine owing to their scalable and cost effective preparation and physiochemical features (high specific surface area, ease in conjugation to peptides/antibodies/proteins and biocompatibility). However, the limited fabrication, functionalization, and in vivo functionalities available in literature indicate inconsistencies regarding the factors affecting in vivo metabolisms, biodistribution as well as toxicity patterns of graphene. It appears that redox signaling pathways, and their proper use to target specific diseases and to improve biocompatibility and interplay between size and optical properties are key determinants to investigate the metabolic fate of such materials. This featured letter provides key insights into the significance and multifunctional roles of redox regulated species in graphene-based materials which can be used to closely mimic therapeutic functions, navigating new paths to nanomedicine and synthetic biology. Furthermore, this letter focuses on the missing functionalities and challenges in using graphene-based materials as both nano-carriers and nano-drugs in various biomedical sectors which might be favorable for multiple payloads and drug targeting in upcoming years.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

miR-93-5p suppresses cellular senescence by directly targeting Bcl-w and p21

Highlights: • Overexpression of Bcl-w promoted activities of SA-ß-gal and H3K9me3. • Bcl-w induced expressions of senescence-related proteins. • In this study, we investigated the mechanism of Bcl-w-induced premature cellular senescence in GBM and lung cancer cells. Cellular senescence, a distinctive type of irreversible growth arrest, develops in response to various stimuli. Bcl-w, an oncogene and member of the Bcl-2 family, has been reported to promote tumorigenicity in various cancer cells. Here, we sought to explore the potential role of Bcl-w in premature senescence, which has received relatively little research attention. Our findings demonstrate that Bcl-w enhances the activity of senescence-associated β-galactosidase (SA-β-gal) and promotes histone H3 tri-methylation at lysine 9 (H3K9me3) and expressions of p53, Notch2, p21, and p16—hallmarks of the senescent phenotype—in human U251 glioblastoma and H460 lung carcinoma cells. It is also known that microRNAs (miRNAs) regulate processes related to tumor development, such as cell proliferation, differentiation, survival, metabolism, inflammation, invasion, angiogenesis, and senescence. In this context, we found that miR-93-5p inhibited premature cellular senescence by directly suppressing Bcl-w and p21 expressions. Collectively, these findings suggest that targeting miR-93-5p–regulated Bcl-w may be a useful strategy for preventing premature senescence.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Clinically relevant concentration of anti-viral drug ribavirin selectively targets pediatric osteosarcoma and increases chemosensitivity

Highlights: • Ribavirin selectively targets osteosarcoma in vitro and in vivo. • Ribavirin acts synergistically with doxorubicin in osteosarcoma. • Ribavirin targets osteosarcoma largely via inhibiting eIF4E. • eIF4E depletion overcomes osteosarcoma chemoresistance. Ribavirin is an anti-viral drug but has recently gained attention as a potential candidate for cancer treatment. In line with these efforts, our work is the first to demonstrate that ribavirin, at clinically relevant concentration, selectively targets pediatric osteosarcoma and increases chemosensitivity. Using preclinical osteosarcoma cell and xenograft models, we found that ribavirin is active against osteosarcoma bulk and subpopulations with highly proliferative and invasive properties via inhibiting growth, inducing apoptosis and suppressing colony formation. At the same concentrations, ribavirin either did not or affected human normal osteoblastic cell and fibroblast cells in a less extent than osteosarcoma cells. Notably, the combination of ribavirin with doxorubicin resulted in greater efficacy than single drug alone. The combination completely arrested the osteosarcoma growth in vivo throughout the whole duration of drug treatment. We further showed that ribavirin acted on osteosarcoma largely via targeting eIF4E. In addition to eIF4E, ribavirin also modulated phosphorylation of Erk and expression of EZH2 and Snail without affecting Akt and mTOR. Lastly, we found that eIF4E expression and phosphorylation were elevated in osteosarcoma compared to normal cells, which might explain the selective anti-osteosarcoma activity of ribavirin. eIF4E depletion mimics the inhibitory effects of ribavirin, further confirm that eIF4E is the essential target of ribavirin in osteosarcoma. Our work provides fundamental evidence of repurposing ribavirin for the treatment of osteosarcoma. Our findings also highlight the therapeutic value of inhibiting eIF4E in osteosarcoma.

60 APPLIED LIFE SCIENCES↗