scholarly journals RBM5-AS1 promotes radioresistance in medulloblastoma through stabilization of SIRT6 protein

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Chuanying Zhu ◽  
Keke Li ◽  
Mawei Jiang ◽  
Siyu Chen
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Xenograft Model ◽  
Clonogenic Survival ◽  
In Vivo Studies ◽  
Radiation Induced ◽  
Non Coding Rnas ◽  
Potential Strategy ◽  
Induced Apoptosis

AbstractCancer stem cells (CSCs) contribute to radioresistance in medulloblastoma. Thus, identification of key regulators of medulloblastoma stemness is critical for improving radiotherapy for medulloblastoma. In the present study, we profiled CSC-related long non-coding RNAs (lncRNAs) between radioresistant and parental medulloblastoma cells. The roles of the lncRNA RBM5-AS1 in the stemness and radiosensitivity of medulloblastoma cells were investigated. We found that RBM5-AS1, a novel inducer of medulloblastoma stemness, was significantly upregulated in radioresistant medulloblastoma cells compared to parental cells. Knockdown of RBM5-AS1 diminished the viability and clonogenic survival of both radioresistant and parental medulloblastoma cells after radiation. Silencing of RBM5-AS1 significantly enhanced radiation-induced apoptosis and DNA damage. In vivo studies confirmed that depletion of RBM5-AS1 inhibited tumor growth and increased radiosensitivity in a medulloblastoma xenograft model. In contrast, overexpression of RBM5-AS1 reduced radiation-induced apoptosis and DNA damage in medulloblastoma cells. Mechanistically, RBM5-AS1 interacted with and stabilized sirtuin 6 (SIRT6) protein. Silencing of SIRT6 reduced the stemness and reinforced radiation-induced DNA damage in medulloblastoma cells. Overexpression of SIRT6 rescued medulloblastoma cells from RBM5-AS1 depletion-induced radiosensitization and DNA damage. Overall, we identify RBM5-AS1 as an inducer of stemness and radioresistance in medulloblastoma. Targeting RBM5-AS1 may represent a potential strategy to overcome the resistance to radiotherapy in this malignancy.

scholarly journals Drosophila p53 directs nonapoptotic programs in postmitotic tissue

2019 ◽  
Vol 30 (11) ◽  
pp. 1339-1351 ◽  
Author(s):  
Paula Kurtz ◽  
Amanda E. Jones ◽  
Bhavana Tiwari ◽  
Nichole Link ◽  
Annika Wylie ◽  
...  
Keyword(s):  
Dna Damage ◽  
Chromatin Immunoprecipitation ◽  
In Vivo Studies ◽  
Rna Seq ◽  
Radiation Induced ◽  
Cell Death Gene ◽  
Apoptotic Genes ◽  
Genome Scale ◽  
Target Activation

TP53 is the most frequently mutated gene in human cancers, and despite intensive research efforts, genome-scale studies of p53 function in whole animal models are rare. The need for such in vivo studies is underscored by recent challenges to established paradigms, indicating that unappreciated p53 functions contribute to cancer prevention. Here we leveraged the Drosophila system to interrogate p53 function in a postmitotic context. In the developing embryo, p53 robustly activates important apoptotic genes in response to radiation-induced DNA damage. We recently showed that a p53 enhancer (p53RErpr) near the cell death gene reaper forms chromatin contacts and enables p53 target activation across long genomic distances. Interestingly, we found that this canonical p53 apoptotic program fails to activate in adult heads. Moreover, this failure to exhibit apoptotic responses was not associated with altered chromatin contacts. Instead, we determined that p53 does not occupy the p53RErpr enhancer in this postmitotic tissue as it does in embryos. Through comparative RNA-seq and chromatin immunoprecipitation–seq studies of developing and postmitotic tissues, we further determined that p53 regulates distinct transcriptional programs in adult heads, including DNA repair, metabolism, and proteolysis genes. Strikingly, in the postmitotic context, p53-binding landscapes were poorly correlated with nearby transcriptional effects, raising the possibility that p53 enhancers could be generally acting through long distances.

Targeting cancer stem cells with a pan-BCL-2 inhibitor in preclinical and clinical settings in patients with gastroesophageal carcinoma

Gut ◽  
2021 ◽  
pp. gutjnl-2020-321175
Author(s):  
Shumei Song ◽  
Qiongrong Chen ◽  
Yuan Li ◽  
Guang Lei ◽  
Ailing Scott ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Antitumour Activity ◽  
Clinical Specimen ◽  
Therapy Resistance ◽  
In Vivo Studies ◽  
Induced Apoptosis

ObjectiveGastro-oesophageal cancers (GEC) are resistant to therapy and lead to poor prognosis. The cancer stem cells (CSCs) and antiapoptotic pathways often confer therapy resistance. We sought to elucidate the antitumour action of a BCL-2 inhibitor, AT101 in GEC in vitro, in vivo and in a clinical trial.MethodsExtensive preclinical studies in vitro and in vivo were carried out to establish the mechanism action of AT101 on targeting CSCs and antiapoptotic proteins. A pilot clinical trial in patients with GEC was completed with AT-101 added to standard chemoradiation.ResultsOverexpression of BCL-2 and MCL-1 was noted in gastric cancer tissues (GC). AT-101 induced apoptosis, reduced proliferation and tumour sphere formation in MCL-1/BCL-2 high GC cells. Interestingly, AT101 dramatically downregulated genes (YAP-1/Sox9) that control CSCs in GEC cell lines regardless of BCL-2/MCL-1 expression. Addition of docetaxel to AT-101 amplified its antiproliferation and induced apoptosis effects. In vivo studies confirmed the combination of AT101 and docetaxel demonstrated stronger antitumour activity accompanied with significant decrease of CSCs biomarkers (YAP1/SOX9). In a pilot clinical trial, 13 patients with oesophageal cancer (EC) received AT101 orally concurrently with chemoradiation. We observed dramatic clinical complete responses and encouraging overall survival in these patients. Clinical specimen analyses revealed that AT-101 dramatically reduced the expression of CSCs genes in treated EC specimens indicating antitumour activity of AT101 relies more on its anti-CSCs activity.ConclusionsOur preclinical and clinical data suggest that AT-101 overcomes resistance by targeting CSCs pathways suggesting a novel mechanism of action of AT101 in patients with GEC.

scholarly journals LINC00115 promotes stemness and inhibits apoptosis of ovarian cancer stem cells by upregulating SOX9 and inhibiting the Wnt/β-catenin pathway through competitively binding to microRNA-30a

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Rui Hou ◽  
Luo Jiang
Keyword(s):  
Ovarian Cancer ◽  
Stem Cells ◽  
Dna Damage ◽  
Caspase 3 ◽  
Gene Expression Omnibus ◽  
Ovarian Cancer Stem Cells ◽  
Non Coding Rnas ◽  
Microarray Datasets ◽  
Cell Supernatant

Abstract Objective Long non-coding RNAs (lncRNAs) and microRNAs (miRs) are differentially expressed in ovarian cancer (OC) cells and influence OC progression. This study intended to explore the underlying roles of LINC00115 and miR-30a in OC. Methods Gene Expression Omnibus database was used to find OC microarray datasets and bioinformatics analysis predicted the potential molecular mechanism of OC. OC stem cells (OCSCs) surface marker was isolated from human OC cell line and identified. CD133+ OCSCs were transfected with LINC00115, miR-30a and SOX9 alone or together to detect sphere-forming ability and apoptosis of OCSCs. Caspase-3 activity and DNA damage in cell supernatant were detected. The levels of CD44, NANOG, POU5F1, LINC00115, CD133, miR-30a and SOX9 were measured. Then sh-LNC00115-treated OCSCs were added with Wnt/β-catenin activator SKL2001 to observe the changes of cell stemness and activity. Finally, animal models were established to evaluate the effect of LINC00115 on OCSC in vivo. Results LINC00115 and SOX9 were highly expressed in OC, while miR-30a was lowly expressed. After silencing LINC00115 or overexpressing miR-30a, the sphere-forming rate of CD133+ OCSC and levels of CD133, CD44, NANOG and POU5F1 decreased, while apoptotic rate, Caspase-3 activity and histone-related DNA damage increased. SOX9 reversed these trends. Additionally, LINC00115 could bind to miR-30a and miR-30a could target SOX9. SKL2001 partially reversed cell stemness and activity in sh-LNC00115-treated OCSCs. Finally, silencing LINC00115 could inhibit OCSCs growth in vivo. Conclusion LINC00115 promoted stemness and inhibited apoptosis of OCSCs by upregulating SOX9 and in activating the Wnt/β-catenin pathway through competitively binding to miR-30a.

scholarly journals Adipose-derived stem cells alleviate radiation-induced dermatitis by suppressing apoptosis and downregulating cathepsin F expression

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Chaoling Yao ◽  
Yue Zhou ◽  
Hui Wang ◽  
Feiyan Deng ◽  
Yongyi Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Western Blotting ◽  
In Vivo Studies ◽  
Adipose Derived Stem Cells ◽  
Skin Damage ◽  
Radiation Induced ◽  
Cathepsin F ◽  
Apoptotic Proteins

Abstract Background Radiation-induced dermatitis is a serious side effect of radiotherapy, and very few effective treatments are currently available for this condition. We previously demonstrated that apoptosis is an important feature of radiation-induced dermatitis and adipose-derived stem cells (ADSCs) are one of the most promising types of stem cells that have a protective effect on acute radiation-induced dermatitis. Cathepsin F (CTSF) is a recently discovered protein that plays an important role in apoptosis. In this study, we investigated whether ADSCs affect chronic radiation-induced dermatitis, and the underlying mechanisms involved. Methods ADSCs were isolated from male Sprague-Dawley (SD) rats and characterized. For in vivo studies, rats were randomly divided into control and ADSC-treated groups, and cultured ADSCs were transplanted into radiation-induced dermatitis model rats. The effects of ADSC transplantation were determined by skin damage scoring, histopathological analysis, electron microscopy, immunohistochemical staining, and western blotting analysis of apoptosis-related proteins. To evaluate the effects of ADSCs in vitro, radiation-induced apoptotic cells were treated with ADSC culture supernatant, and apoptosis-related protein expression was investigated by TUNEL staining, flow cytometry, and western blotting. Results In the in vivo studies, skin damage, inflammation, fibrosis, and apoptosis were reduced and hair follicle and sebaceous gland regeneration were enhanced in the ADSC group compared with the control group. Further, CTSF and downstream pro-apoptotic proteins (Bid, BAX, and caspase 9) were downregulated, while anti-apoptotic proteins (Bcl-2 and Bcl-XL) were upregulated. In vitro, ADSCs markedly attenuated radiation-induced apoptosis, downregulated CTSF and downstream pro-apoptotic proteins, and upregulated anti-apoptotic proteins. Conclusion ADSCs protect against radiation-induced dermatitis by exerting an anti-apoptotic effect through inhibition of CTSF expression. ADSCs may be a good therapeutic candidate to prevent the development of radiation-induced dermatitis.

scholarly journals PDTM-34. RADIOSENSITIZATION BY BRD4 INHIBITION IN DIFFUSE INTRINSIC PONTINE GLIOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi194-vi195
Author(s):  
Takahiro Sasaki ◽  
Hiroaki Katagi ◽  
Dusten Unruh ◽  
Stewart Goldman ◽  
Lihua Zou ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Clonogenic Survival ◽  
Strand Break ◽  
Diffuse Intrinsic Pontine Glioma ◽  
In Vivo Studies ◽  
Pontine Glioma ◽  
Dsb Repair ◽  
Radiation Induced ◽  
Brd4 Inhibition

Abstract Diffuse intrinsic pontine glioma (DIPG), the most frequent brainstem tumor in pediatrics, is one of the devastating childhood cancers, and virtually all patients die within two years after diagnosis. Since these tumors occur in the brainstem which is vital area, there are no surgical options for providing relief to patients, and conventional chemotherapy as well as radiation therapy provides palliative relief at best. DIPG shows increased H3 K27 acetylation (H3K27ac), which binds to BET bromodomain protein 4 (BRD4) and they are strongly associated with active transcription. Here we tested the hypothesis that BRD4 inhibition by JQ1 enhances radiation-induced DNA damage, making it a potential radiosensitizer in the treatment of DIPG. We evaluated the effects of JQ1 on genes expression using RNA sequence. Radiation-induced DNA double-strand break (DSB) repair was analyzed by immunocytochemistry and western blotting of DSB markers γH2AX and 53BP1, and DSB repair markers pRad50 and Rad51. Clonogenic survival assay was used to determine the effect of JQ1 on radiation response of DIPG cells. In vivo response to radiation monotherapy and combination therapy of RT and JQ1 were evaluated in patient-derived DIPG xenografts. JQ1 significantly reduced the expression of DNA DSB repair genes in DIPG cells. JQ1 sustained high levels of γH2AX and 53BP1 and reduced the levels of pRad50 and Rad51 in irradiated DIPG cells. JQ1 reduced clonogenic survival and enhanced radiation effect in DIPG cells. In vivo studies revealed increased survival of animals treated with combination therapy of RT and JQ1 in compared to either monotherapy. Together, these results highlight JQ1 as a potential radiosensitizer and provide a rationale for developing combination therapy with radiation in the treatment of DIPG.

scholarly journals Raddeanin a Suppresses Glioblastoma Growth by Inducing ROS Generation and Subsequent JNK Activation to Promote Cell Apoptosis

2018 ◽  
Vol 47 (3) ◽  
pp. 1108-1121 ◽  
Author(s):  
Fei Peng ◽  
Xiaoxiong Wang ◽  
Mengting Shu ◽  
Mingfei Yang ◽  
Ligang Wang ◽  
...  
Keyword(s):  
Xenograft Model ◽  
Ros Generation ◽  
Transmission Electron ◽  
Glioma Xenograft ◽  
Potential Strategy ◽  
Underlying Mechanisms ◽  
Induced Apoptosis ◽  
Hoechst Staining ◽  
Jnk Activation

Background/Aims: Raddeanin A (RA), an active pharmacological ingredient from Anemone raddeana Regel, plays an important role in tumor suppression. In this study, we assessed the potentially therapeutic effect of RA on glioblastoma and its underlying mechanisms. Methods: Cell viability was examined using the MTT assay. Invasive and migratory capacities were examined using Transwell and wound healing assays. Apoptosis was determined by Hoechst staining, flow cytometry, DCFH-fluorescent probe and immunohistochemical staining. Autophagy was detected by transmission electron microscopy and western blotting. A U251 glioma xenograft model was established to evaluate the effect of RA in vivo. Results: The data demonstrated that RA inhibited viability, and abrogated the invasive/migratory abilities of glioblastoma cells. In addition, RA induced apoptosis by reactive oxygen species (ROS)/ Jun N-terminal kinase (JNK) signaling in glioblastoma. Conversely, the antioxidant N-Acetyl-L-cysteine (NAC) and pan-caspase inhibitor z-VAD-fmk attenuated RA-induced apoptosis by scavenging ROS and inactivating caspase-3. Furthermore, the inhibition of autophagy by 3-MA exacerbated apoptosis through ROS generation and JNK phosphorylation. In vivo, RA exhibited a curative effect on U251-derived xenografts in nude mice. Conclusions: The results of this study suggest that RA suppressed the growth of glioblastoma, thus serving as a promising and potential strategy for glioblastoma chemotherapy.

scholarly journals Photoprotective Effect Of Stilbenes And Its Derivatives against Ultraviolet Radiation-Induced Skin Disorders

2018 ◽  
Vol 11 (3) ◽  
pp. 1199-1208 ◽  
Author(s):  
Tava Shelan Nagapan ◽  
Ahmad Rohi Ghazali ◽  
Dayang Fredalina Basri ◽  
Wenna Nallance Lim
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Ultraviolet Radiation ◽  
Biological Activities ◽  
In Vivo Studies ◽  
Skin Disorders ◽  
Cutaneous Toxicity ◽  
Radiation Induced

Ultraviolet radiation (UVR) from sunlight is an environmental human carcinogen. Skin exposure to UVR would increase the oxidative stress, deoxyribonucleic acid (DNA) damage, melanogenesis and photocarcinogenesis. Therefore, development of photoprotective agent is necessary in order to reduce the cutaneous toxicity. The use natural active compounds like stilbenes and its derivatives have gained attention as photoprotection to skin due to its broad biological activities such as antioxidant, anti-inflammatory, anti melanogenesis and chemoprevention. This review article aims to analyse the existing literature on the photoprotective effect of stilbenes and its derivatives which include the resveratrol, pterostilbene, piceatannol and oxyresveratrol on in vitro and in vivo studies. This article describes the stilbenes and its derivatives protect and prevent UVR induced skin disorders via the reduction of oxidative stress, alleviation of DNA damage, inhibition of melanogenesis and anti photocarcinogenic effect.

scholarly journals 18 Peroxiredoxin1 is a therapeutic target in group-3 medulloblastoma

2018 ◽  
Vol 45 (S3) ◽  
pp. S16-S16
Author(s):  
BV. Sajesh ◽  
OH. Ngoc ◽  
R. Omar ◽  
H. Fediuk ◽  
L. Li ◽  
...  
Keyword(s):  
Dna Damage ◽  
Therapeutic Target ◽  
Oxidative Dna Damage ◽  
Tumor Burden ◽  
In Vivo Studies ◽  
Orthotopic Model ◽  
Group 3 ◽  
Induced Apoptosis

Group-3 medulloblastoma (MBL) is highly resistant to radiation (IR) and chemotherapy and has the worst prognosis. Hence, there is an urgent need to elucidate targets that sensitize these tumors to chemotherapy and IR. Employing standard assays for viability and sensitization to IR, we identified PRDX1 as a therapeutic target in Group-3 MBL. Specifically, targeting PRDX1 by RNAi or inhibition by Adenanthin led to specific killing and sensitization to IR of Group-3 MBL cells. We rescued sensitization of Daoy and UW228 cells by hypermorphic expression of PRDX1. PRDX1 knockdown caused oxidative DNA damage and induced apoptosis. We correlated PRDX1 expression to patient outcomes in a validated MBL tumor-microarray. Whole genome sequencing identified pathways/genes that were dysregulated with PRDX1 inhibition or silencing. Our in vivo studies in mice employing flank/orthotopic tumors from patient derived xenografts/Group-3 MBL cells confirmed in vitro observations. Animals with tumors in which PRDX1 was targeted by RNAi or Adenanthin (using mini osmotic pumps) showed decreased tumor burden and increased survival when compared to controls. Since, Adenanthin does not cross the blood brain barrier (BBB) we used HAV6 peptide to transiently disrupt the BBB and deliver Adenanthin to the tumor. Immunohistochemistry confirmed that targeting PRDX1 resulted in increased oxidative DNA damage, apoptosis and decreased proliferation. In summary, we have validated PRDX1 as a therapeutic target in group-3 MBL, identified Adenanthin as a potent chemical inhibitor of PRDX1 and confirmed the role of HAV peptide (in the transient modulation of BBB permeability) in an orthotopic model of group-3 MBL.

scholarly journals Downregulation of CDC20 Increases Radiosensitivity through Mcl-1/p-Chk1-Mediated DNA Damage and Apoptosis in Tumor Cells

2020 ◽  
Vol 21 (18) ◽  
pp. 6692
Author(s):  
Yang Gao ◽  
Pengbo Wen ◽  
Bin Chen ◽  
Guanshuo Hu ◽  
Lijun Wu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Direct Interaction ◽  
In Vivo Studies ◽  
Glutathione S Transferase ◽  
Cancer Radiotherapy ◽  
Apoptotic Signaling ◽  
Damage Repair ◽  
Radiation Induced ◽  
Apoptotic Pathways

Radiotherapy is an important modality for the local control of human cancers, but the radioresistance induced by aberrant apoptotic signaling is a hallmark of cancers. Restoring the aberrant apoptotic pathways is an emerging strategy for cancer radiotherapy. In this study, we determined that targeting cell division cycle 20 (CDC20) radiosensitized colorectal cancer (CRC) cells through mitochondrial-dependent apoptotic signaling. CDC20 was overexpressed in CRC cells and upregulated after radiation. Inhibiting CDC20 activities genetically or pharmacologically suppressed the proliferation and increased radiation-induced DNA damage and intrinsic apoptosis in CRC cells. Mechanistically, knockdown of CDC20 suppressed the expression of antiapoptotic protein Mcl-1 but not other Bcl-2 family proteins. The expressions of CDC20 and Mcl-1 respond to radiation simultaneously through direct interaction, as evidenced by immunoprecipitation and glutathione S-transferase (GST) pull-down assays. Subsequently, decreased Mcl-1 expression inhibited the expression level of phosphorylated checkpoint kinase 1 (p-Chk1), thereby resulting in impaired DNA damage repair through downregulating the homologous recombination repair protein Rad51 and finally causing apoptotic signaling. In addition, both CDC20 and Chk1 inhibitors together, through in vivo studies, confirmed the radiosensitizing effect of CDC20 via inhibiting Mcl-1 and p-Chk1 expression. In summary, our results indicate that targeting CDC20 is a promising strategy to improve cancer radiotherapy.

scholarly journals Selective Targeting of Breast Cancer by Tafuramycin a Using SMA-Nanoassemblies

Molecules ◽  
2021 ◽  
Vol 26 (12) ◽  
pp. 3532
Author(s):  
Ibrahim M. El-Deeb ◽  
Valeria Pittala ◽  
Diab Eltayeb ◽  
Khaled Greish
Keyword(s):  
Breast Cancer ◽  
Progesterone Receptors ◽  
In Vivo Studies ◽  
Chemotherapy Agent ◽  
Anticancer Effects ◽  
Tumor Tissues ◽  
Potential Strategy ◽  
Tumor Accumulation

Triple-negative breast cancer (TNBC) is a heterogeneous subtype of tumors that tests negative for estrogen receptors, progesterone receptors, and excess HER2 protein. The mainstay of treatment remains chemotherapy, but the therapeutic outcome remains inadequate. This paper investigates the potential of a duocarmycin derivative, tafuramycin A (TFA), as a new and more effective chemotherapy agent in TNBC treatment. To this extent, we optimized the chemical synthesis of TFA, and we encapsulated TFA in a micellar system to reduce side effects and increase tumor accumulation. In vitro and in vivo studies suggest that both TFA and SMA–TFA possess high anticancer effects in TNBC models. Finally, the encapsulation of TFA offered a preferential avenue to tumor accumulation by increasing its concentration at the tumor tissues by around four times in comparison with the free drug. Overall, the results provide a new potential strategy useful for TNBC treatment.

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