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https://www.readbyqxmd.com/read/29777201/novel-smoothened-inhibitors-for-therapeutic-targeting-of-na%C3%A3-ve-and-drug-resistant-hedgehog-pathway-driven-cancers
#1
Qing-Rou Li, Hui Zhao, Xue-Sai Zhang, Henk Lang, Ker Yu
The G protein-coupled receptor (GPCR) smoothened (SMO) is a key signaling component of the sonic hedgehog (Hh) pathway and a clinically validated target for cancer treatment. The FDA-approved SMO inhibitors GDC-0449/Vismodegib and LDE225/Sonidegib demonstrated clinical antitumor efficacy. Nevertheless, relatively high percentage of treated patients would eventually develop acquired cross resistance to both drugs. Here, based on published structure and activity of GDC-0449 inhibitor class, we replaced its amide core with benzimidazole which retained bulk of the SMO-targeting activity as measured in our Hh/SMO/Gli1-reporter system...
May 18, 2018: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/29757673/rapamycin-insensitive-mechanistic-target-of-rapamycin-regulates-basal-and-resistance-exercise-induced-muscle-protein-synthesis
#2
Riki Ogasawara, Takeshi Suginohara
We investigated whether rapamycin-insensitive mechanistic target of rapamycin (mTOR) signaling plays a role in regulating resistance exercise-induced muscle protein synthesis. We used a rodent model of resistance exercise and compared the effect of rapamycin, an allosteric mTOR inhibitor, with the effect of AZD8055, an ATP-competitive mTOR kinase inhibitor. The right gastrocnemius muscle of male Sprague-Dawley rats age 11 wk was contracted isometrically via percutaneous electrical stimulation (100 Hz, 5 sets of ten 3-s contractions, 7 s of rest between contractions, 3 min of rest between sets), and the left gastrocnemius muscle served as control...
May 14, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29757257/mtor-pathway-in-papillary-thyroid-carcinoma-different-contributions-of-mtorc1-and-mtorc2-complexes-for-tumor-behavior-and-slc5a5-mrna-expression
#3
Catarina Tavares, Catarina Eloy, Miguel Melo, Adriana Gaspar da Rocha, Ana Pestana, Rui Batista, Luciana Bueno Ferreira, Elisabete Rios, Manuel Sobrinho Simões, Paula Soares
The mammalian target of rapamycin (mTOR) pathway is overactivated in thyroid cancer (TC). We previously demonstrated that phospho-mTOR expression is associated with tumor aggressiveness, therapy resistance, and lower mRNA expression of SLC5A5 in papillary thyroid carcinoma (PTC), while phospho-S6 (mTORC1 effector) expression was associated with less aggressive clinicopathological features. The distinct behavior of the two markers led us to hypothesize that mTOR activation may be contributing to a preferential activation of the mTORC2 complex...
May 13, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29755672/inhibition-of-mtor-complex-2-restrains-tumor-angiogenesis-in-multiple-myeloma
#4
Aurelia Lamanuzzi, Ilaria Saltarella, Vanessa Desantis, Maria Antonia Frassanito, Patrizia Leone, Vito Racanelli, Beatrice Nico, Domenico Ribatti, Paolo Ditonno, Marcella Prete, Antonio Giovanni Solimando, Francesco Dammacco, Angelo Vacca, Roberto Ria
The mammalian Target of Rapamycin (mTOR) is an intracellular serine/threonine kinase that mediates intracellular metabolism, cell survival and actin rearrangement. mTOR is made of two independent complexes, mTORC1 and mTORC2, activated by the scaffold proteins RAPTOR and RICTOR, respectively. The activation of mTORC1 triggers protein synthesis and autophagy inhibition, while mTORC2 activation promotes progression, survival, actin reorganization, and drug resistance through AKT hyper-phosphorylation on Ser473...
April 17, 2018: Oncotarget
https://www.readbyqxmd.com/read/29752943/distinct-notch-signaling-expression-patterns-between-nucleoside-and-nucleotide-analogues-treatment-for-hepatitis-b-virus-infection
#5
Zijing Wang, Kazunori Kawaguchi, Masao Honda, Yoshio Sakai, Tatsuya Yamashita, Eishiro Mizukoshi, Shuichi Kaneko
Nucleos(t)ide analogues therapies are currently approved for the treatment of chronic hepatitis B virus (HBV) infection, which effectively suppress HBV replication and correlate with the anti-HBV-specific immune response. Notch signaling serves pleiotropic roles in the immune system that also contribute to virus-specific immunity. In this study, we assessed Notch signal-related gene expression after administrating nucleoside or nucleotide analogues to HBV-replicating cells and clinical liver tissues. We found distinct Notch signaling expression patterns under nucleos(t)ide analogues therapies, with high expression for nucleotide analogues (adefovir pivoxil or tenofovir disoproxil fumarate) and low expression for nucleoside analogues (lamivudine or entecavir) in the presence of HBV infection...
May 9, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29750193/mammalian-eak-7-activates-alternative-mtor-signaling-to-regulate-cell-proliferation-and-migration
#6
Joe Truong Nguyen, Connor Ray, Alexandra Lucienne Fox, Daniela Baccelli Mendonça, Jin Koo Kim, Paul H Krebsbach
Nematode EAK-7 (enhancer-of- akt -1-7) regulates dauer formation and controls life span; however, the function of the human ortholog mammalian EAK-7 (mEAK-7) is unknown. We report that mEAK-7 activates an alternative mechanistic/mammalian target of rapamycin (mTOR) signaling pathway in human cells, in which mEAK-7 interacts with mTOR at the lysosome to facilitate S6K2 activation and 4E-BP1 repression. Despite interacting with mTOR and mammalian lethal with SEC13 protein 8 (mLST8), mEAK-7 does not interact with other mTOR complex 1 (mTORC1) or mTOR complex 2 (mTORC2) components; however, it is essential for mTOR signaling at the lysosome...
May 2018: Science Advances
https://www.readbyqxmd.com/read/29736310/depletion-of-gamma-glutamylcyclotransferase-in-cancer-cells-induces-autophagy-followed-by-cellular-senescence
#7
Keiko Taniguchi, Kengo Matsumura, Hiromi Ii, Susumu Kageyama, Eishi Ashihara, Tokuhiro Chano, Akihiro Kawauchi, Tatsuhiro Yoshiki, Susumu Nakata
Gamma-glutamylcyclotransferase (GGCT) was originally identified as a protein highly expressed in bladder cancer tissues by proteomic analysis, and its higher expression in a variety of cancers compared to normal tissues have been shown. Depletion of GGCT in various cancer cells results in antiproliferative effects both in vitro and in vivo ; thus it is considered a promising therapeutic target. Although it has been shown that knockdown of GGCT induces cellular senescence and non-apoptotic cell death, associated with upregulation of cyclin-dependent kinase inhibitors (CDKIs) including p21WAF1/CIP1 , the cellular events that follow GGCT depletion are not fully understood...
2018: American Journal of Cancer Research
https://www.readbyqxmd.com/read/29731844/combining-the-mammalian-target-of-rapamycin-inhibitor-rapamycin-with-resveratrol-has-a-synergistic-effect-in-multiple-myeloma
#8
Hong-Guang Jin, Guo-Zhen Wu, Guo-Hua Wu, Yong-Ge Bao
Rapamycin is known to inhibit the mammalian target of rapamycin complex (mTORC)1 signaling pathway, but it is unable to effectively inhibit mTORC2, resulting in activation of protein kinase B in multiple myeloma (MM) cell lines. Additionally, certain studies have suggested that resveratrol has an effect on human MM cells, and that rapamycin in combination with resveratrol may be useful in cancer therapy. The present study aimed to investigate the combined treatment effect of resveratrol and rapamycin on the MM MM1...
May 2018: Oncology Letters
https://www.readbyqxmd.com/read/29724916/inhibition-of-foxo1-transcription-factor-in-primary-human-adipocytes-mimics-the-insulin-resistant-state-of-type-2-diabetes
#9
Meenu R Rajan, Elin Nyman, Cecilia Brännmark, Charlotta S Olofsson, Peter Strålfors
Type 2 diabetes is characterized by insulin resistance in the expanding adipose tissue of obesity. The insulin resistance manifests in human adipocytes as system-wide impairment of insulin signalling. An exception is regulation of transcription factor FOXO1, which is phosphorylated downstream of mTORC2 and is therefore not exhibiting impaired response to insulin. However, the abundance, and activity, of FOXO1 is reduced by half in adipocytes from patients with diabetes. To elucidate the effect of reduced FOXO1 activity, we herein transduced human adipocytes with a dominant-negative construct of FOXO1 (DN-FOXO1)...
May 3, 2018: Biochemical Journal
https://www.readbyqxmd.com/read/29720580/targeting-mtorc1-2-complexes-inhibit-tumorigenesis-and-enhance-sensitivity-to-5-flourouracil-5-fu-in-hepatocellular-carcinoma-a-preclinical-study-of-mtorc1-2-targeted-therapy-in-hepatocellular-carcinoma-hcc
#10
Yu Zhang, Qing-An Jia, Dhruba Kadel, Xiao-Fei Zhang, Quan-Bao Zhang
BACKGROUND Although 5-Flourouracil(5-FU) is used as the first-choice treatment for advanced hepatocellular carcinoma (HCC), it is associated with acquired and intrinsic resistance. Hyperactivation of mTOR signaling has been linked to tumorigenesis and chemoresistance in HCC. The aim of this study was to evaluate and compare the antitumor effects of mTORC1 inhibitor everolimus and mTORC1/2 inhibitor AZD8055 and to examine the interaction between 5-FU and mTORC1/2 inhibitor in HCC. MATERIAL AND METHODS Using cultured HCC cells and mouse xenograft, the antitumor effects of everolimus and AZD8055 were analyzed as mono- and combination therapy with 5-Flourouracil...
May 3, 2018: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/29692710/pp242-counteracts-glioblastoma-cell-proliferation-migration-invasiveness-and-stemness-properties-by-inhibiting-mtorc2-akt
#11
Carmen Mecca, Ileana Giambanco, Stefano Bruscoli, Oxana Bereshchenko, Bernard Fioretti, Carlo Riccardi, Rosario Donato, Cataldo Arcuri
Glioblastoma multiforme (GBM) is the most malignant brain tumor and is associated with poor prognosis due to its thorny localization, lack of efficacious therapies and complex biology. Among the numerous pathways driving GBM biology studied so far, PTEN/phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT/mechanistic target of rapamycin (mTOR) signaling plays a pivotal role, as it controls cell survival, proliferation and metabolism and is involved in stem cell maintenance. In front of recent and numerous evidences highlighting mTOR upregulation in GBM, all the strategies developed to inhibit this pathway have been substantially unsuccessful...
2018: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/29660598/first-in-human-phase-1-dose-escalation-pharmacokinetic-and-pharmacodynamic-study-of-the-oral-dual-pi3k-and-mtorc1-2-inhibitor-pqr309-in-patients-with-advanced-solid-tumors-sakk-67-13
#12
Andreas Wicki, Nicholas Brown, Alexandros Xyrafas, Vincent Bize, Hanne Hawle, Simona Berardi, Nataša Cmiljanović, Vladimir Cmiljanović, Michael Stumm, Saša Dimitrijević, Richard Herrmann, Vincent Prêtre, Reto Ritschard, Alexandar Tzankov, Viviane Hess, Alexa Childs, Cinta Hierro, Jordi Rodon, Dagmar Hess, Markus Joerger, Roger von Moos, Cristiana Sessa, Rebecca Kristeleit
BACKGROUND: PQR309 is an orally bioavailable, balanced pan-phosphatidylinositol-3-kinase (PI3K), mammalian target of rapamycin (mTOR) C1 and mTORC2 inhibitor. PATIENTS AND METHODS: This is an accelerated titration, 3 + 3 dose-escalation, open-label phase I trial of continuous once-daily (OD) PQR309 administration to evaluate the safety, pharmacokinetics (PK) and pharmacodynamics in patients with advanced solid tumours. Primary objectives were to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D)...
April 13, 2018: European Journal of Cancer
https://www.readbyqxmd.com/read/29660335/mtor-up-regulation-of-bex4-promotes-lung-adenocarcinoma-cell-proliferation-by-potentiating-oct4
#13
Ziran Zhao, Jiagen Li, Fengwei Tan, Shugeng Gao, Jie He
Previously, BEX family members have been reported to participate in cancer development. However, little is known about the role of BEX4 in lung adenocarcinoma (LAC). Here, we found that BEX4 was over-expressed in LAC tissues compared with adjacent tissues. LAC tissues from metastatic patients exhibited higher expression of BEX4 comparing to those from non-metastatic ones. In vitro, BEX4 ectopic expression accelerated the proliferation of both A549 and H1975 cells. By contrast, knockdown of BEX4 suppressed the proliferation of A549 and H1975 cells...
April 13, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29625858/m2-polarization-of-macrophages-by-oncostatin-m-in-hypoxic-tumor-microenvironment-is-mediated-by-mtorc2-and-promotes-tumor-growth-and-metastasis
#14
Richa Shrivastava, Mohammad Asif, Varsha Singh, Parul Dubey, Showkat Ahmad Malik, Mehraj-U-Din Lone, Brij Nath Tewari, Khemraj Singh Baghel, Subhashis Pal, Geet Kumar Nagar, Naibedya Chattopadhyay, Smrati Bhadauria
Oncostatin M (OSM), an inflammatory cytokine belonging to the interleukin-6 (IL-6) superfamily, plays a vital role in multitude of physiological and pathological processes. Its role in breast tumor progression and metastasis to distant organs is well documented. Recent reports implicate OSM in macrophage M2 polarization, a key pro-tumoral phenomenon. M2 polarization of macrophages is believed to promote tumor progression by potentiating metastasis and angiogenesis. In the current study, we delineated the mechanism underlying OSM induced macrophage M2 polarization...
April 3, 2018: Cytokine
https://www.readbyqxmd.com/read/29621478/hyperglycemia-induced-bcl-2-bax-mediated-apoptosis-of-schwann-cells-via-mtorc1-s6k1-inhibition-in-diabetic-peripheral-neuropathy
#15
Lin Zhu, Jun Hao, Meijuan Cheng, Cuihong Zhang, Chunxiu Huo, Yaping Liu, Wei Du, Xianghong Zhang
Schwann cell apoptosis is one of the characteristics of diabetic peripheral neuropathy (DPN). The mammalian target of rapamycin (mTOR) is a multifunctional signaling pathway that regulates cell apoptosis in various types of tissues and cells. To investigate whether the mTOR pathway is involved in cell apoptosis in the Schwann cells of DPN, diabetic mice and rat Schwann cells (RSC96) were chosen to detect phospho-mTOR (Ser 2448), phospho-S6K1 (Thr 389), phospho-4EBP1 (Thr 37/46), Bcl-2, Bax and cleaved caspase-3 by diverse pathological and biological techniques...
June 15, 2018: Experimental Cell Research
https://www.readbyqxmd.com/read/29617677/the-mtor-kinase-inhibitor-cz415-inhibits-human-papillary-thyroid-carcinoma-cell-growth
#16
Xiaobin Li, Zongze Li, Yimin Song, Wenjing Liu, Ziwen Liu
BACKGROUND/AIM: Mammalian target of rapamycin (mTOR) plays an important role in papillary thyroid carcinoma (PTC) cell progression. CZ415 is a novel, highly-efficient and specific mTOR kinase inhibitor. The current study tested the potential anti-tumor activity of CZ415 in human PTC cells. METHODS: The established (TPC-1 cell line) and primary human PTC cells were treated with CZ415. Cell survival and growth were tested by Cell Counting Kit-8 assay and BrdU ELISA assay, respectively...
March 28, 2018: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29611762/-guaiol-regulates-autophagic-cell-death-depending-on-mtor-signaling-in-nsclc
#17
Xiaohui Yang, Jiabei Zhu, Jianchun Wu, Nan Huang, Zhongqi Cui, Yingbin Luo, Fenyong Sun, Qiuhui Pan, Yan Li, Qingyuan Yang
(-)-Guaiol, a sesquiterpene alcohol with the guaiane skeleton, has been found in many Chinese medicinal plants and been reported to comprise various guaiane natural products that are well known for their antibacterial activities. Previously, we have shown its antitumor activity by inducing autophagy in NSCLC cells. However, its potential mechanism in inducing autophagy is still under our investigation. Here, data from our western blotting assays showed that, in NSCLC cells, (-)-Guaiol significantly blocked the mTORC2-AKT signaling by suppressing mTOR phosphorylation at serine 2481 (S2481) to induce autophagy, illustrated by the increasing ratio of LC3II/I...
April 3, 2018: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/29581766/large-intergenic-non-coding-rna-ror-inhibits-aerobic-glycolysis-of-glioblastoma-cells-via-akt-pathway
#18
Yong Li, Zhi-Cheng He, Qing Liu, Kai Zhou, Yu Shi, Xiao-Hong Yao, Xia Zhang, Hsiang-Fu Kung, Yi-Fang Ping, Xiu-Wu Bian
Reprogramming energy metabolism is a hallmark of malignant tumors, including glioblastoma (GBM). Aerobic glycolysis is often utilized by tumor cells to maintain survival and proliferation. However, the underlying mechanisms of aerobic glycolysis in GBM remain elusive. Herein, we demonstrated that large intergenic non-coding RNA-RoR (LincRNA-RoR) functioned as a critical suppressor to inhibit the aerobic glycolysis and viability of GBM cells. We found that LincRNA-RoR was markedly reduced in GBM tissues compared with adjacent non-tumor tissues from 10 cases of GBM patients...
2018: Journal of Cancer
https://www.readbyqxmd.com/read/29571732/induction-of-mek-erk-activity-by-azd8055-confers-acquired-resistance-in-neuroblastoma
#19
Dong-Qing Xu, Hidemi Toyoda, Lei Qi, Mari Morimoto, Ryo Hanaki, Shotaro Iwamoto, Yoshihiro Komada, Masahiro Hirayama
Mammalian target of rapamycin (mTOR) complex (mTORC) is frequently activated in diverse cancers. Although dual mTORC1/2 inhibitors are currently under development to treat various malignancies, the emergence of drug resistance has proven to be a major complication. AZD8055 is a novel, potent ATP-competitive and specific inhibitor of mTOR kinase activity, which blocks both mTORC1 and mTORC2 activation. In this study, we acquired AZD8055-resistant neuroblastoma (NB) cell sublines by using prolonged stepwise escalation of AZD8055 exposure (4-12 weeks)...
March 20, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29567957/cryo-em-structure-of-human-mtor-complex-2
#20
Xizi Chen, Mengjie Liu, Yuan Tian, Jiabei Li, Yilun Qi, Dan Zhao, Zihan Wu, Min Huang, Catherine C L Wong, Hong-Wei Wang, Jiawei Wang, Huirong Yang, Yanhui Xu
Mechanistic target of rapamycin (mTOR) complex 2 (mTORC2) plays an essential role in regulating cell proliferation through phosphorylating AGC protein kinase family members, including AKT, PKC and SGK1. The functional core complex consists of mTOR, mLST8, and two mTORC2-specific components, Rictor and mSin1. Here we investigated the intermolecular interactions within mTORC2 complex and determined its cryo-electron microscopy structure at 4.9 Å resolution. The structure reveals a hollow rhombohedral fold with a 2-fold symmetry...
March 22, 2018: Cell Research
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