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Rapamycin increases oxidative stress response gene expression in adult stem cells

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Rapamycin increases oxidative stress response gene expression in adult stem cells Abstract Balancing quiescence with proliferation is of paramount importance for adult stem cells in order to avoid hyperproliferation and cell depletion. In some models, stem cell exhaustion may be reversed with the drug rapamycin, which was shown can suppress cellular senescence  in vitro  and extend lifespan in animals. We hypothesized that rapamycin increases the expression of oxidative stress response genes in adult stem cells, and that these gene activities diminish with age. To test our hypothesis, we exposed mice to rapamycin and then examined the transcriptome of their spermatogonial stem cells (SSCs). Gene expression microarray analysis revealed that numerous oxidative stress response genes were upregulated upon rapamycin treatment, including superoxide dismutase 1, glutathione reductase, and delta-aminolevulinate dehydratase. When we examined the expression of these genes in 55-week-old wild typ
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Stress Response of Glioblastoma Cells Mediated by miR-17-5p Targeting PTEN and the Passenger Strand miR-17-3p Targeting MDM2

Stress Response of Glioblastoma Cells Mediated by miR-17-5p Targeting PTEN and the Passenger Strand miR-17-3p Targeting MDM2 ABSTRACT Tumor development not only destroys the homeostasis of local tissues but also the whole body, and thus the tumor cells have to face the body’s defense system, a shortage of nutrition and oxygen, and chemotherapeutic drug treatment. In response to these stresses, tumor cells often alter gene expression and microRNA levels to facilitate survival. We have demonstrated that glioblastoma cells deprived of nutrition or treated with chemotherapeutics drugs expressed increased levels of miR-17. Ectopic transfection of miR-17 prolonged glioblastoma cell survival when the cells were deprived with nutrition or treated with chemotherapeutic drugs. Expression of miR-17 also promoted cell motility, invasion, and tube-like structure formation. We found that these phenotypes were the results of miR-17 targeting PTEN. As a consequence, HIF1α and VEGF were up-regulated. E
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Development of an orally-administrative MELK-targeting inhibitor that suppresses the growth of various types of human cancer

Development of an orally-administrative MELK-targeting inhibitor that suppresses the growth of various types of human cancer ABSTRACT We previously reported MELK (maternal embryonic leucine zipper kinase) as a novel therapeutic target for breast cancer. MELK was also reported to be highly upregulated in multiple types of human cancer. It was implied to play indispensable roles in cancer cell survival and indicated its involvement in the maintenance of tumor-initiating cells. We conducted a high-throughput screening of a compound library followed by structure-activity relationship studies, and successfully obtained a highly potent MELK inhibitor OTSSP167 with IC 50  of 0.41 nM. OTSSP167 inhibited the phosphorylation of PSMA1 (proteasome subunit alpha type 1) and DBNL (drebrin-like), which we identified as novel MELK substrates and are important for stem-cell characteristics and invasiveness. The compound suppressed mammosphere formation of breast cancer cells and exhibited significant t
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A combination of temsirolimus, an allosteric mTOR inhibitor, with clofarabine as a new therapeutic option for patients with acute myeloid leukemia

A combination of temsirolimus, an allosteric mTOR inhibitor, with clofarabine as a new therapeutic option for patients with acute myeloid leukemia ABSTRACT Signaling through the phosphatidylinositol 3-kinase (PI3K) pathway and its downstream effectors, Akt and mechanistic target of rapamycin (mTOR), is aberrantly activated in acute myeloid leukemia (AML) patients, where it contributes to leukemic cell proliferation, survival, and drug-resistance. Thus, inhibiting mTOR signaling in AML blasts could enhance their sensitivity to cytotoxic agents. Preclinical data also suggest that allosteric mTOR inhibition with rapamycin impaired leukemia initiating cells (LICs) function. In this study, we assessed the therapeutic potential of a combination consisting of temsirolimus [an allosteric mTOR complex  1  (mTORC 1 ) inhibitor] with clofarabine, a nucleoside analogue with potent inhibitory effects on both ribonucleotide reductase and DNA polymerase. The drug combination (CLO-TOR) displayed syner
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Small-molecule inhibition of BRD4 as a new potent approach to eliminate leukemic stem- and progenitor cells in acute myeloid leukemia (AML)

Small-molecule inhibition of BRD4 as a new potent approach to eliminate leukemic stem- and progenitor cells in acute myeloid leukemia (AML) ABSTRACT Acute myeloid leukemia (AML) is a life-threatening stem cell disease characterized by uncontrolled proliferation and accumulation of myeloblasts. Using an advanced RNAi screen-approach in an AML mouse model we have recently identified the epigenetic ‘reader’ BRD4 as a promising target in AML. In the current study, we asked whether inhibition of BRD4 by a small-molecule inhibitor, JQ1, leads to growth-inhibition and apoptosis in primary human AML stem- and progenitor cells. Primary cell samples were obtained from 37 patients with freshly diagnosed AML (n=23) or refractory AML (n=14). BRD4 was found to be expressed at the mRNA and protein level in unfractionated AML cells as well as in highly enriched CD34 + /CD38 -  and CD34 + /CD38 +  stem- and progenitor cells in all patients examined. In unfractionated leukemic cells, submicromolar conce
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Down-regulation of Sox7 is associated with aberrant activation of Wnt/β-catenin signaling in endometrial cancer

Down-regulation of Sox7 is associated with aberrant activation of Wnt/β-catenin signaling in endometrial cancer ABSTRACT Although the mortality rate of endometrial cancer is comparatively low in gynecologic malignancies, a rising trend of this cancer has been observed for the past decade. The understanding of the molecular mechanism will favor for the clinical management of this disease. Aberrant activation of Wnt/β-catenin signaling pathway plays a major role in the pathogenesis of endometrioid adenocarcinoma including this cancer type. In this study, we reported that Sox7, one of Sox transcriptional factors, was frequently underexpressed in endometrial cancer and importantly, it was associated with dysregulation of the Wnt/β-catenin signaling activity. Immunohistochemical and quantitative RT-PCR analyses showed that Sox7 was underexpressed and was associated with high-grade tumor ( P =0.021), increased expressions of β-catenin ( P =0.038) and its downstream targets; CyclinD1 ( P <
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Rapamycin: Killing two birds with one stone

Rapamycin: Killing two birds with one stone Inhibition of TOR signaling leads to extended longevity in both invertebrate and invertebrate species by modulating a number of downstream molecular pathways [1,2]. Drugs that inhibit the TOR pathway can serve as powerful tools to translate the effects of the TOR pathway on lifespan in simpler invertebrate model systems to more complex systems like mammals. One of the most promising drugs to slow aging is rapamycin, an inhibitor of TOR, which was previously shown to extend lifespan in mice when administered late in life [3]. As aging is one of the biggest risk factors for cancer, one of the outstanding questions is whether drugs that slow aging will also slow age-related increases in cancer incidence. A recent study describes how treatment of mice initiated early in life can not only retard aging but also slow age-related increase in cancer. Work by Anisimov and colleagues examines the impact on health and lifespan of Rapamycin treated inbred
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