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https://www.readbyqxmd.com/read/28437835/pten-downregulation-promotes-%C3%AE-oxidation-to-fuel-hypertrophic-liver-growth-after-hepatectomy-in-mice
#1
Ekaterina Kachaylo, Christoph Tschuor, Nicolas Calo, Nathalie Borgeaud, Perparim Limani, Anne-Christine Piguet, Jean-Francois Dufour, Michelangelo Foti, Rolf Graf, Pierre A Clavien, Bostjan Humar
In regenerating liver, hepatocytes accumulate lipids before the major wave of parenchymal growth. This transient, regeneration-associated steatosis (TRAS) is required for liver recovery, but its purpose is unclear. The tumor suppressor PTEN is a key inhibitor of the AKT-mTOR axis that regulates growth and metabolic adaptations after hepatectomy. In quiescent liver, PTEN causes pathological steatosis when lost, while its role in regenerating liver remains unknown. Here, we show that PTEN downregulation promotes liver growth in a TRAS-dependent way...
April 24, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28435223/efficacy-of-the-dual-pi3k-and-mtor-inhibitor-nvp-bez235-in-combination-with-imatinib-mesylate-against-chronic-myelogenous-leukemia-cell-lines
#2
Pengliang Xin, Chuntuan Li, Yan Zheng, Qunyi Peng, Huifang Xiao, Yuanling Huang, Xiongpeng Zhu
BACKGROUND: Phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway is a therapy target of cancer. We aimed to confirm the effect of dual PI3K/mTOR inhibitor NVP-BEZ235 on proliferation, apoptosis, and autophagy of chronic myelogenous leukemia (CML) cells and sensitivity of tyrosine kinase inhibitor in vitro. METHODS: Two human CML cell lines, K562 and KBM7R (T315I mutant strain), were used. The proliferation of CML cells was detected by MTS (Owen's reagent) assay...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/28434143/the-mtor-signaling-pathway-in-myocardial-dysfunction-in-type-2-diabetes-mellitus
#3
REVIEW
Tomohiro Suhara, Yuichi Baba, Briana K Shimada, Jason K Higa, Takashi Matsui
PURPOSE OF REVIEW: T2DM (type 2 diabetes mellitus) is a risk factor for heart failure. The mTOR (mechanistic target of rapamycin) is a key mediator of the insulin signaling pathway. We will discuss the role of mTOR in myocardial dysfunction in T2DM. RECENT FINDINGS: In T2DM, chronically activated mTOR induces multiple pathological events, including a negative feedback loop that suppresses IRS (insulin receptor substrate)-1. While short-term treatment with rapamycin, an mTOR inhibitor, is a promising strategy for cardiac diseases such as acute myocardial infarction and cardiac hypertrophy in T2DM, there are many concerns about chronic usage of rapamycin...
June 2017: Current Diabetes Reports
https://www.readbyqxmd.com/read/28433890/il-37-induces-autophagy-in-hepatocellular-carcinoma-cells-by-inhibiting-the-pi3k-akt-mtor-pathway
#4
Ting-Ting Li, Di Zhu, Tong Mou, Zhen Guo, Jun-Liang Pu, Qing-Song Chen, Xu-Fu Wei, Zhong-Jun Wu
Autophagy is an intracellular "self-eating" process that is closely related to inflammation and cellular immunity. New studies indicate that autophagy is also involved in tumor suppression. The anti-inflammatory cytokine interleukin-37 (IL-37) has been shown to have tumor-suppressive abilities in hepatocellular carcinoma (HCC). Notably, autophagy appears to play a dual role in the development of HCC and may be involved in both tumorigenesis and tumor suppression. However, the potential role of IL-37 in autophagy is currently unknown...
April 20, 2017: Molecular Immunology
https://www.readbyqxmd.com/read/28432555/rotundarpene-inhibits-tnf-%C3%AE-induced-activation-of-the-akt-mtor-and-nf-%C3%AE%C2%BAb-pathways-and-the-jnk-and-p38-associated-with-production-of-reactive-oxygen-species
#5
Arum Kim, Yoon Jeong Nam, Yong Kyoo Shin, Min Sung Lee, Dong Suep Sohn, Chung Soo Lee
Ilex Rotunda Thunb has been shown to have anti-inflammatory and antioxidant effects. In human keratinocytes, we investigated the effect of rotundarpene (4-caffeoyl-3-methyl-but-2-ene-1,4-diol) on the TNF-α-stimulated production of inflammatory mediators in relation to the Akt, mTOR, and NF-κB pathways, and the JNK and p38-MAPK. Rotundarpene, Akt inhibitor, Bay 11-7085, rapamycin, and N-acetylcysteine inhibited the TNF-α-stimulated production of cytokines and chemokines, increase in the levels of p-Akt and mTOR, activation of NF-κB, and production of reactive oxygen species in keratinocytes...
April 21, 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/28430863/fgfr2-amplification-in-metastatic-hormone-positive-breast-cancer-and-response-to-an-mtor-inhibitor
#6
Lironne Wein, Peter Savas, Courtney Van Geelan, Franco Caramia, Kate Moodie, Sachin Joshi, Sherene Loi
No abstract text is available yet for this article.
April 18, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28427860/differential-mtor-pathway-profiles-in-bladder-cancer-cell-line-subtypes-to-predict-sensitivity-to-mtor-inhibition
#7
Andrew M Hau, Manando Nakasaki, Kazufumi Nakashima, Goutam Krish, Donna E Hansel
BACKGROUND: Molecular classification of bladder cancer has been increasingly proposed as a potential tool to predict clinical outcomes and responses to chemotherapy. Here we focused on mechanistic target of rapamycin (mTOR) inhibition as a chemotherapeutic strategy and characterized the expression profile of mTOR signaling targets in representative bladder cancer cell lines from basal, luminal, and either basal/luminal ("non-type") molecular subtypes. MATERIALS AND METHODS: Protein and mRNA expression of mTOR signaling components from representative luminal (RT4 and RT112), basal (SCaBER and 5637), and nontype (T24 and J82) bladder cancer cell line subtypes were determined by Western blot and database mining analysis of the Cancer Cell Line Encyclopedia...
April 18, 2017: Urologic Oncology
https://www.readbyqxmd.com/read/28427207/mir-205-inhibits-cell-growth-by-targeting-akt-mtor-signaling-in-progesterone-resistant-endometrial-cancer-ishikawa-cells
#8
Zhihong Zhuo, Huimin Yu
PURPOSE: miR-205 is significantly up-regulated in endometrioid adenocarcinoma. In this study, the significant anticancer effect of a miR-205 inhibitor was investigated in both endometrial carcinoma and progesterone-resistant endometrial carcinoma cells. RESULTS: Compared with Ishikawa endometrial cancer cells, miR-205 was expressed at higher levels in a progesterone-resistant (PR) sub-cell line. Inhibition of miR-205 suppressed the growth of cancer cells in a dose- and time-dependent manner...
March 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/28424584/hif-1%C3%AE-overexpression-improves-transplanted-bone-mesenchymal-stem-cells-survival-in-rat-mcao-stroke-model
#9
Bingke Lv, Feng Li, Jianbang Han, Jie Fang, Limin Xu, Chengmei Sun, Tian Hua, Zhongfei Zhang, Zhiming Feng, Xiaodan Jiang
Bone mesenchymal stem cells (BMSCs) death after transplantation is a serious obstacle impacting on the outcome of cell therapy for cerebral infarction. This study was aimed to investigate whether modification of BMSCs with hypoxia-inducible factor 1α (Hif-1α) could enhance the survival of the implanted BMSCs. BMSCs were isolated from Wistar rats, and were infected with Hif-1α-GFP lentiviral vector or Hif-1α siRNA. The modified BMSCs were exposed to oxygen-glucose deprivation (OGD) condition, cellular viability and apoptosis were then assessed...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28424411/migration-pattern-actin-cytoskeleton-organization-and-response-to-pi3k-mtor-and-hsp90-inhibition-of-glioblastoma-cells-with-different-invasive-capacities
#10
Simon Memmel, Dmitri Sisario, Caren Zöller, Vanessa Fiedler, Astrid Katzer, Robin Heiden, Nicholas Becker, Lorenz Eing, Fábio L R Ferreira, Heiko Zimmermann, Markus Sauer, Michael Flentje, Vladimir L Sukhorukov, Cholpon S Djuzenova
High invasiveness and resistance to chemo- and radiotherapy of glioblastoma multiforme (GBM) make it the most lethal brain tumor. Therefore, new treatment strategies for preventing migration and invasion of GBM cells are needed. Using two different migration assays, Western blotting, conventional and super-resolution (dSTORM) fluorescence microscopy we examine the effects of the dual PI3K/mTOR-inhibitor PI-103 alone and in combination with the Hsp90 inhibitor NVP-AUY922 and/or irradiation on the migration, expression of marker proteins, focal adhesions and F-actin cytoskeleton in two GBM cell lines (DK-MG and SNB19) markedly differing in their invasive capacity...
April 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/28423691/predicting-clinical-benefit-from-everolimus-in-patients-with-advanced-solid-tumors-the-cpct-03-study
#11
Fleur Weeber, Geert A Cirkel, Marlous Hoogstraat, Sander Bins, Christa G M Gadellaa-van Hooijdonk, Salo Ooft, Erik van Werkhoven, Stefan M Willems, Marijn van Stralen, Wouter B Veldhuis, Nicolle J M Besselink, Hugo M Horlings, Neeltje Steeghs, Maja J de Jonge, Marlies H G Langenberg, Lodewyk F A Wessels, Edwin P J G Cuppen, J H Schellens, Stefan Sleijfer, Martijn P Lolkema, Emile E Voest
BACKGROUND: In this study, our aim was to identify molecular aberrations predictive for response to everolimus, an mTOR inhibitor, regardless of tumor type. METHODS: To generate hypotheses about potential markers for sensitivity to mTOR inhibition, drug sensitivity and genomic profiles of 835 cell lines were analyzed. Subsequently, a multicenter study was conducted. Patients with advanced solid tumors lacking standard of care treatment options were included and underwent a pre-treatment tumor biopsy to enable DNA sequencing of 1,977 genes, derive copy number profiles and determine activation status of pS6 and pERK...
March 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28423618/mir-363-3p-inhibits-tumor-growth-by-targeting-pcna-in-lung-adenocarcinoma
#12
Yahong Wang, Ting Chen, Haili Huang, Yun Jiang, Lawei Yang, Ziying Lin, Huijuan He, Tie Liu, Bin Wu, Jie Chen, David W Kamp, Gang Liu
Increasing evidence suggests that microRNAs play key roles in lung cancer. Our previous study demonstrated that microRNA 363-3p (miR-363-3p) is downregulated in lung cancer tissues. In this study, we demonstrated that overexpression of miR-363-3p inhibits the proliferation and colony formation of A549 and H441 cells, while silencing of miR-363-3p has the converse effects. The anti-oncogenic function of miR-363-3p was verified in a mouse tumor xenograft model. Furthermore, cell cycle analysis showed miR-363-3p can induce S phase arrest by downregulating Cyclin-D1 and upregulating Cyclin-dependent kinase-2 in lung adenocarcinoma cells...
March 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/28423589/role-of-microrna-21-in-radiosensitivity-in-non-small-cell-lung-cancer-cells-by-targeting-pdcd4-gene
#13
Li-Peng Jiang, Chun-Yan He, Zhi-Tu Zhu
This study aims to explore the effects of microRNA-21 (miR-21) on radiosensitivity in non-small cell lung cancer (NSCLC) by targeting programmed cell deanth 4 (PDCD4) and regulating PI3K/AKT/mTOR signaling pathway. Cancer tissues and adjacent normal tissues were collected from 97 NSCLC patients who received a standard radiotherapy regimen. TUNEL assay was applied to determine cell apoptosis in tissues. The qRT-PCR assay was used to detect the expressions of miR-21 expression and PDCD4 mRNA. The protein expressions of PDCD4 and PI3K/AKT/mTOR signaling pathway-related proteins were determined by Western blotting...
April 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28423515/preclinical-therapeutic-efficacy-of-a-novel-blood-brain-barrier-penetrant-dual-pi3k-mtor-inhibitor-with-preferential-response-in-pi3k-pten-mutant-glioma
#14
Dimpy Koul, Shuzhen Wang, Shaofang Wu, Norihiko Saito, Siyuan Zheng, Feng Gao, Isha Kaul, Masaki Setoguchi, Kiyoshi Nakayama, Kumiko Koyama, Yoshinobu Shiose, Erik P Sulman, Yasuhide Hirota, W K Alfred Yung
Glioblastoma (GBM) is an ideal candidate disease for signal transduction targeted therapy because the majority of these tumors harbor genetic alterations that result in aberrant activation of growth factor signaling pathways. Loss of heterozygosity of chromosome 10, mutations in the tumor suppressor gene PTEN, and PI3K mutations are molecular hallmarks of GBM and indicate poor prognostic outcomes in many cancers. Consequently, inhibiting the PI3K pathway may provide therapeutic benefit in these cancers. PI3K inhibitors generally block proliferation rather than induce apoptosis...
March 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28423496/mtor-inhibitors-activate-perk-signaling-and-favor-viability-of-gastrointestinal-neuroendocrine-cell-lines
#15
Patricia Freis, Julien Bollard, Justine Lebeau, Patrick Massoma, Joëlle Fauvre, Cécile Vercherat, Thomas Walter, Serge Manié, Colette Roche, Jean-Yves Scoazec, Carole Ferraro-Peyret
mTOR and Unfolded Protein Response (UPR) are two signaling pathways frequently activated in cancer cells. The mTOR pathway has been shown to be up-regulated in most gastroenteropancreatic neuroendocrine tumors. In contrast, little is known about the UPR status in neoplastic neuroendocrine cells. However, these hormone-producing cells are likely to present distinctive adaptations of this pathway, as other secretory cells. We therefore analyzed the status of the three axes of UPR and their relation to mTOR pathway in two gastrointestinal neuroendocrine tumors (GI-NET) cell lines STC-1 and GluTag...
March 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28423208/combined-activity-of-temozolomide-and-the-mtor-inhibitor-temsirolimus-in-metastatic-melanoma-involves-dkk1
#16
Heike Niessner, Corinna Kosnopfel, Tobias Sinnberg, Daniela Beck, Kathrin Krieg, Ines Wanke, Konstantinos Lasithiotakis, Michael Bonin, Claus Garbe, Friedegund Meier
The BRAFV600E inhibitor vemurafenib achieves remarkable clinical responses in patients with BRAF-mutant melanoma, but its effects are limited by the onset of drug resistance. In the case of resistance, chemotherapy can still be applied as second line therapy. However, it yields low response rates and strategies are urgently needed to potentiate its effects. In a previous study, we showed that the inhibition of the PI3K-AKT-mTOR pathway significantly increases sensitivity of melanoma cells to chemotherapeutic drugs (1)...
April 19, 2017: Experimental Dermatology
https://www.readbyqxmd.com/read/28420429/deptor-maintains-plasma-cell-differentiation-and-favorably-affects-prognosis-in-multiple-myeloma
#17
Dalia Quwaider, Luis A Corchete, Irena Misiewicz-Krzeminska, María E Sarasquete, José J Pérez, Patryk Krzeminski, Noemí Puig, María Victoria Mateos, Ramón García-Sanz, Ana B Herrero, Norma C Gutiérrez
BACKGROUND: The B cell maturation process involves multiple steps, which are controlled by relevant pathways and transcription factors. The understanding of the final stages of plasma cell (PC) differentiation could provide new insights for therapeutic strategies in multiple myeloma (MM). Here, we explore the role of DEPTOR, an mTOR inhibitor, in the terminal differentiation of myeloma cells, and its potential impact on patient survival. METHODS: The expression level of DEPTOR in MM cell lines and B cell populations was measured by real-time RT-PCR, and/or Western blot analysis...
April 18, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28418837/rapamycin-promotes-differentiation-increasing-%C3%AE-iii-tubulin-neun-and-neurod-while-suppressing-nestin-expression-in-glioblastoma-cells
#18
Michela Ferrucci, Francesca Biagioni, Paola Lenzi, Stefano Gambardella, Rosangela Ferese, Maria Teresa Calierno, Alessandra Falleni, Alfonso Grimaldi, Alessandro Frati, Vincenzo Esposito, Cristina Limatola, Francesco Fornai
Glioblastoma cells feature mammalian target of rapamycin (mTOR) up-regulation which relates to a variety of effects such as: lower survival, higher infiltration, high stemness and radio- and chemo-resistance. Recently, it was demonstrated that mTOR may produce a gene shift leading to altered protein expression. Therefore, in the present study we administered different doses of the mTOR inhibitor rapamycin to explore whether the transcription of specific genes are modified. By using a variety of methods we demonstrate that rapamycin stimulates gene transcription related to neuronal differentiation while inhibiting stemness related genes such as nestin...
March 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28417284/a-phase-i-dose-escalation-study-of-the-safety-and-pharmacokinetics-of-a-tablet-formulation-of-voxtalisib-a-phosphoinositide-3-kinase-inhibitor-in-patients-with-solid-tumors
#19
Janice M Mehnert, Gerald Edelman, Mark Stein, Heather Camisa, Joanne Lager, Jean-François Dedieu, Anne-Frédérique Ghuysen, Jyoti Sharma, Li Liu, Patricia M LoRusso
Background Voxtalisib, a PI3K/mTOR inhibitor, has shown antitumor activity in capsule formulation in patients with solid tumors. This Phase I study assessed safety and pharmacokinetics of voxtalisib administered as immediate-release tablets in patients with solid tumors (NCT01596270). Methods A "3 + 3" dose escalation design was used. Adverse events (AEs), pharmacokinetics (PK), food effect and tumor response were evaluated. Results Thirty-two patients received voxtalisib doses ranging from 50 mg to 70 mg once daily (QD) and 17 patients received voxtalisib doses ranging from 30 mg to 50 mg twice daily (BID), for two 28-day cycles...
April 17, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28416797/unification-of-de-novo-and-acquired-ibrutinib-resistance-in-mantle-cell-lymphoma
#20
Xiaohong Zhao, Tint Lwin, Ariosto Silva, Bijal Shah, Jiangchuan Tao, Bin Fang, Liang Zhang, Kai Fu, Chengfeng Bi, Jiannong Li, Huijuan Jiang, Mark B Meads, Timothy Jacobson, Maria Silva, Allison Distler, Lancia Darville, Ling Zhang, Ying Han, Dmitri Rebatchouk, Maurizio Di Liberto, Lynn C Moscinski, John M Koomen, William S Dalton, Kenneth H Shain, Michael Wang, Eduardo Sotomayor, Jianguo Tao
The novel Bruton's tyrosine kinase inhibitor ibrutinib has demonstrated high response rates in B-cell lymphomas; however, a growing number of ibrutinib-treated patients relapse with resistance and fulminant progression. Using chemical proteomics and an organotypic cell-based drug screening assay, we determine the functional role of the tumour microenvironment (TME) in ibrutinib activity and acquired ibrutinib resistance. We demonstrate that MCL cells develop ibrutinib resistance through evolutionary processes driven by dynamic feedback between MCL cells and TME, leading to kinome adaptive reprogramming, bypassing the effect of ibrutinib and reciprocal activation of PI3K-AKT-mTOR and integrin-β1 signalling...
April 18, 2017: Nature Communications
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