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Mtor akt independent

Biao Xie, Ke Cao, Jinjin Li, Jia Chen, Jintian Tang, Xiang Chen, Kun Xia, Xiao Zhou, Yan Cheng, Jianda Zhou, Huiqing Xie
The molecular and cellular mechanisms behind the involvement of inflammation in melanoma have not been fully elucidated. In this study, knockdown of Hmgb1 expression increased apoptosis, reduced invasion and p-NF-κB expression, but increased Klotho protein level in melanoma tumor cells. The effect of Hmgb1 knockdown was overcome by LPS. Introduction of exogenous Hmgb1 significantly decreased apoptosis, increased invasion, elevated p-NF-κB, but lowered Klotho protein level in melanoma cells. The effect of exogenous Hmgb1 was agonized by NF-κB inhibitor CAPE...
October 13, 2016: Oncotarget
Yingying Liu, Shanshan Fang, Qiushi Sun, Bo Liu
Glioblastoma is one of the most vascular brain tumour and highly resistant to current therapy. Targeting both glioblastoma cells and angiogenesis may present an effective therapeutic strategy for glioblastoma. In our work, we show that an anthelmintic drug, ivermectin, is active against glioblastoma cells in vitro and in vivo, and also targets angiogenesis. Ivermectin significantly inhibits growth and anchorage-independent colony formation in U87 and T98G glioblastoma cells. It induces apoptosis in these cells through a caspase-dependent manner...
October 19, 2016: Biochemical and Biophysical Research Communications
Lee M Margolis, Donato A Rivas, Maria Berrone, Yassine Ezzyat, Andrew J Young, James P McClung, Roger A Fielding, Stefan M Pasiakos
Short-term (5-10 days) calorie restriction (CR) downregulates muscle protein synthesis, with consumption of a high protein-based diet attenuating this decline. Benefit of increase protein intake is believed to be due to maintenance of amino acid-mediated anabolic signaling through the mechanistic target of rapamycin complex 1 (mTORC1), however, there is limited evidence to support this contention. The purpose of this investigation was to determine the effects of prolonged CR and high protein diets on skeletal muscle mTORC1 signaling and expression of associated microRNA (miR)...
2016: Frontiers in Physiology
Chen Hongbo, Duo Yanhong, Hu Bo, Wang Zhiwei, Zhang Fang, Tsai Hsiangi, Zhang Jianping, Zhou Lanzhen, Wang Lijun, Wang Xinyu, Huang Laiqiang
PICT-1 was originally identified as a tumor suppressor. Here, we found that PICT-1 overexpression triggered pro-death autophagy without nucleolar disruption or p53 accumulation in U251 and MCF7 cells. Truncated PICT-1 fragments 181-346 and 1-346, which partly or totally lack nucleolar localization, showed weaker autophagy-inducing effects than full-length PICT-1 and a well-defined nucleolar mutant (181-479). Furthermore, PICT-1 partly localizes to the nucleolar fibrillar center (FC) and directly binds to ribosomal DNA (rDNA) gene loci, where it interacts with upstream binding factor (UBF)...
September 27, 2016: Oncotarget
Tamás Sticz, Anna Molnár, Ágnes Márk, Melinda Hajdu, Noémi Nagy, Gyula Végső, Tamás Micsik, László Kopper, Anna Sebestyén
AIMS: Tumour heterogeneity and altered activation of signalling pathways play important roles in therapy resistance. The PI3K/Akt/mTOR signalling network is a well-known regulator of several functions that contribute to tumour growth. mTOR exists in two functionally different multiprotein complexes. We aimed to determine mTOR activity-related proteins in clinically followed, conventionally treated colon carcinomas and to analyse the correlation between clinical data and mTORC1 and mTORC2 activity...
October 11, 2016: Journal of Clinical Pathology
E Müller, S Bauer, T Stühmer, A Mottok, C-J Scholz, T Steinbrunn, D Brünnert, A Brandl, H Schraud, S Kreßmann, A Beilhack, A Rosenwald, R C Bargou, M Chatterjee
Direct therapeutic targeting of oncogenic RAS is currently still impossible due to lack of suitable pharmacological inhibitors. Because specific blockade of druggable RAS effectors might represent an alternative treatment approach, we evaluated the role of the Raf complex for multiple myeloma (MM) pathobiology. We found frequent overexpression of the Raf isoforms (A-, B- and C-Raf) and downstream activation of MEK1,2/ERK1,2 in MM cells. Concomitant inhibition of all Raf isoforms (pan-Raf inhibition) by RNAi or pharmacological inhibitors was required to strongly induce apoptosis in MM cell lines, primary MM cells in vitro, and in a syngeneic MM mouse model in vivo...
September 30, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Zhouqing Huang, Shengjie Wu, Fanqi Kong, Xueli Cai, Bozhi Ye, Peiren Shan, Weijian Huang
MicroRNAs and autophagy play critical roles in cardiac hypoxia/reoxygenation (H/R)-induced injury. Here, we investigated the function of miR-21 in regulating autophagy and identified the potential molecular mechanisms involved. To determine the role of miR-21 in regulating autophagy, H9c2 cells were divided into the following six groups: control group, H/R group, (miR-21+ H/R) group, (miR-21-negative control + H/R) group, (BEZ235+ H/R) group and (miR-21+ BEZ235+ H/R) group. The cells underwent hypoxia for 1 hr and reoxygenation for 3 hrs...
September 29, 2016: Journal of Cellular and Molecular Medicine
Ren-Jie Wei, Su-Shuan Lin, Wen-Ren Wu, Lih-Ren Chen, Chien-Feng Li, Han-De Chen, Chien-Ting Chou, Ya-Chun Chen, Shih-Shin Liang, Shang-Tao Chien, Yow-Ling Shiue
The objective was to investigate the upstream mechanisms of apoptosis which were triggered by a novel anti-microtubule drug, ABT-751, in hepatocellular carcinoma-derived Huh-7 cells. Effects of ABT-751 were evaluated by immunocytochemistry, flow cytometric, alkaline comet, soft agar, immunoblotting, CytoID, green fluorescent protein-microtubule associated protein 1 light chain 3 beta detection, plasmid transfection, nuclear/cytosol fractionation, coimmunoprecipitation, quantitative reverse transcription-polymerase chain reaction, small-hairpin RNA interference and mitochondria/cytosol fractionation assays...
September 24, 2016: Toxicology and Applied Pharmacology
Xiao-Fei Zhang, Le Ou-Yang, Xing-Ming Zhao, Hong Yan
Understanding how the structure of gene dependency network changes between two patient-specific groups is an important task for genomic research. Although many computational approaches have been proposed to undertake this task, most of them estimate correlation networks from group-specific gene expression data independently without considering the common structure shared between different groups. In addition, with the development of high-throughput technologies, we can collect gene expression profiles of same patients from multiple platforms...
September 28, 2016: Scientific Reports
Nazir M Khan, Mohammad Y Ansari, Tariq M Haqqi
Pathogenesis of osteoarthritis (OA) is multifactorial but interleukin-1β (IL-1β) is known to be an important mediator of cartilage degradation. Autophagy is an essential cellular homeostasis mechanism and has been proposed to protect against cartilage degradation and chondrocyte death under pathological conditions. We investigated the role of autophagy activated by sucrose, a natural disaccharide, in suppressing inflammatory mediator's expression and cell death under pathological conditions in human chondrocytes...
September 26, 2016: Journal of Cellular Biochemistry
Ahmet Imrali, Xueying Mao, Marc Yeste-Velasco, Jonathan Shamash, Yongjie Lu
Prostate cancer is the most common malignancy in Western men and hormone refractory cancer (HRPC) kills most of the patients. Chemo-resistance is a major obstacle for the treatment of prostate cancer. Platinum-complexes have been used to treat a number of malignancies including prostate cancer. However, it has limited effect to prostate cancer and with significant toxicity at higher doses. In recent years, increasing numbers of new agents targeting cancer specific pathways have become available and with low toxic side-effects...
2016: American Journal of Cancer Research
Robert Eil, Suman K Vodnala, David Clever, Christopher A Klebanoff, Madhusudhanan Sukumar, Jenny H Pan, Douglas C Palmer, Alena Gros, Tori N Yamamoto, Shashank J Patel, Geoffrey C Guittard, Zhiya Yu, Valentina Carbonaro, Klaus Okkenhaug, David S Schrump, W Marston Linehan, Rahul Roychoudhuri, Nicholas P Restifo
Tumours progress despite being infiltrated by tumour-specific effector T cells. Tumours contain areas of cellular necrosis, which are associated with poor survival in a variety of cancers. Here, we show that necrosis releases intracellular potassium ions into the extracellular fluid of mouse and human tumours, causing profound suppression of T cell effector function. Elevation of the extracellular potassium concentration ([K(+)]e) impairs T cell receptor (TCR)-driven Akt-mTOR phosphorylation and effector programmes...
September 14, 2016: Nature
Ekta Lachmandas, Macarena Beigier-Bompadre, Shih-Chin Cheng, Vinod Kumar, Arjan van Laarhoven, Xinhui Wang, Anne Ammerdorffer, Lily Boutens, Dirk de Jong, Thirumala-Devi Kanneganti, Mark S Gresnigt, Tom H M Ottenhoff, Leo A B Joosten, Rinke Stienstra, Cisca Wijmenga, Stefan H E Kauffman, Reinout van Crevel, Mihai G Netea
Cells in homeostasis metabolise glucose mainly through the tri-carboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS), whilst activated cells switch their basal metabolism to aerobic glycolysis. In thus study, we examined whether metabolic reprogramming towards aerobic glycolysis is important for the host response to Mycobacterium tuberculosis (Mtb). Through transcriptional and metabolite analysis we show that Mtb induces a switch in host cellular metabolism towards aerobic glycolysis in human peripheral blood mononuclear cells (PBMCs)...
September 14, 2016: European Journal of Immunology
Marisa Granato, Celeste Rizzello, Maria Anele Romeo, Shivangi Yadav, Roberta Santarelli, Gabriella D'Orazi, Alberto Faggioni, Mara Cirone
Burkitt's lymphoma is an aggressive B cell lymphoma whose pathogenesis involves mainly c-Myc translocation and hyperexpression, in addition to antigen-independent BCR signaling and, in some cases, EBV infection. As result of BCR signaling activation, the PI3K/AKT/mTOR pathway results constitutively activated also in the absence of EBV, promoting cell survival and counterbalancing the pro-apoptotic function that c-Myc may also exert. In this study we found that quercetin, a bioflavonoid widely distributed in plant kingdom, reduced c-Myc expression and inhibited the PI3K/AKT/mTOR activity in BL, leading to an apoptotic cell death...
October 2016: International Journal of Biochemistry & Cell Biology
Jing Zhao, Shi-Wei Li, Qian-Qian Gong, Ling-Cui Ding, Ye-Cheng Jin, Jian Zhang, Jian-Gang Gao, Xiao-Yang Sun
It is widely accepted that body weight and adipose mass are tightly regulated by homeostatic mechanisms, in which leptin plays a critical role through hypothalamic pathways, and obesity is a result of homeostatic disorder. However, in C57BL/6J mice, we found that Rcan2 increases food intake and plays an important role in the development of age- and diet-induced obesity through a leptin-independent mechanism. RCAN2 was initially identified as a thyroid hormone (T3)-responsive gene in human fibroblasts. Expression of RCAN2 is regulated by T3 through the PI3K-Akt/PKB-mTOR-Rps6kb1 signaling pathway...
September 2016: Journal of Zhejiang University. Science. B
Yang Quan-Jun, Huo Yan, Han Yong-Long, Wan Li-Li, Li Jie, Huang Jin-Lu, Lu Jin, Chen Peng-Guo, Gan Run, Guo Cheng
Cancer cachexia is a multifactorial syndrome affecting the skeletal muscle. Previous clinical trials showed MEK inhibitor selumetinib treatment resulted in skeletal muscle anabolism. However, it is conflicting that MAPK/ERK pathway control mass of skeletal muscle. The present study investigated the therapeutic effect and mechanisms of selumetinib in amelioration of cancer cachexia. The classical cancer cachexia model was established via transplantation of CT26 colon adenocarcinoma into BALB/c mice. The effect of selumetinib on body weight, tumor growth, skeletal muscle, food intake, serum proinflammatory cytokines, E3 ligases and MEK/ERK-related pathways was analyzed...
September 6, 2016: Molecular Cancer Therapeutics
Ruichao Huo, Lili Wang, Peijuan Liu, Yong Zhao, Caiqin Zhang, Bing Bai, Xueying Liu, Changhong Shi, Sanhua Wei, Hai Zhang
Cabazitaxel has been used to treat castration-resistant prostate cancer since its approval by the US Food and Drug Administration in 2010. However, whether cabazitaxel may inhibit the proliferation of other tissue‑derived cancer cells, and its underlying mechanism, remains unknown. In the present study, the A549 lung adenocarcinoma cancer cell line was exposed to cabazitaxel, in order to investigate its cytotoxic effect and determine the underlying mechanism. The results demonstrated that cabazitaxel was able to induce autophagy in A549 cells, as evidenced by the formation of autophagosomes, upregulated LC3‑II expression and increased LC3 puncta...
October 2016: Molecular Medicine Reports
I A Netland, H E Førde, L Sleire, L Leiss, M A Rahman, B S Skeie, C H Gjerde, P Ø Enger, D Goplen
BACKGROUND: Glioblastomas (GBMs) are highly malignant brain tumours with a poor prognosis, and current cytotoxic regimens provide only a limited survival benefit. The PI3K/Akt/mTOR pathway has been an attractive target for therapy due to its high activation in GBMs as well as other cancers. The dual pan-PI3K/mTOR kinase inhibitor dactolisib (NVP-BEZ235) is an anti-neoplastic compound currently under investigation. However, little is known about its efficacy in human GBMs. We aimed at evaluating the efficacy of dactolisib in human glioblastoma cells, as well as in murine models carrying human GBM xenografts...
2016: BMC Cancer
Ju Yong Bae, Ki Ok Shin, Jinhee Woo, Sang Heon Woo, Ki Soeng Jang, Yul Hyo Lee, Sunghwun Kang
PURPOSE: The purpose of this study was to investigate the effect of exercise and dietary change on obesity and insulin resistance and mTOR signaling protein levels in skeletal muscles of obese rats. METHODS: Sixty male Sprague-Dawley rats were divided into CO (Normal diet) and HF (High Fat diet) groups in order to induce obesity for 15 weeks. The rats were then subdivided into CO, COT (CO + Training), HF, HFT (HF + Training), HFND (Dietary change), and HFNDT (HFND + Training) groups (10 rats / group)...
June 2016: Journal of Exercise Nutrition & Biochemistry
Cara M Statz, Sara E Patterson, Susan M Mockus
BACKGROUND: The progression of prostate cancer to castration-resistant prostate cancer (CRPC) is often a result of somatic alterations in the PI3K/Akt/mTOR (mammalian target of rapamycin) pathway, suggesting that therapies targeting this pathway might lead to improved survival and efficacy. Here, we systematically evaluate the results of clinical trials investigating mTOR inhibition in CRPC and utilize preclinical data to predict clinical outcomes. METHODS: Trials included in the study were identified through PubMed and via review of conference abstracts cited by relevant review articles...
August 9, 2016: Targeted Oncology
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