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https://www.readbyqxmd.com/read/28730764/mtor-deregulation-in-oral-cavity-squamous-cell-carcinoma
#1
Nicholas S Mastronikolis, Evangelos Tsiambas, Theodoros A Papadas, Panagiotis P Fotiades, Athanasios T Papadas, Stylianos N Mastronikolis, Ioannis Kastanioudakis, Vasileios Ragos
Signal transduction pathways consist of a variety of inter- and intra-cellular molecules. They act as supporting mechanisms for cell survival and homeostasis. Among them, the phosphatidylinositol 3-kinase (PI3K)/tumor suppressor phosphatase and tensin homologue deleted on chromosome ten (PTEN)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway plays a crucial role in regulating normal cell growth based on growth factor receptors (GFRs) interaction, including epidermal GFR (type II-HER2) and insulin GFR (IGF)...
May 2017: Journal of B.U.ON.: Official Journal of the Balkan Union of Oncology
https://www.readbyqxmd.com/read/28723563/a-positive-feedback-loop-between-sestrin2-and-mtorc2-is-required-for-the-survival-of-glutamine-depleted-lung-cancer-cells
#2
Jun-Kyu Byun, Yeon-Kyung Choi, Ji-Hyun Kim, Ji Yun Jeong, Hui-Jeon Jeon, Mi-Kyung Kim, Ilseon Hwang, Shin-Yup Lee, You Mie Lee, In-Kyu Lee, Keun-Gyu Park
Proper regulation of mTORC1 and mTORC2 upon nutrient starvation is critical for cancer cell survival. Upregulation of Sestrin2 in response to glutamine deprivation rescues cell death by suppressing mTORC1. However, the contribution of mTORC2 to Sestrin2-mediated mTORC1 suppression remains unclear. Here, we report that both Sestrin2 and mTORC2 are upregulated in glutamine-depleted lung cancer cells. Moreover, glutamine depletion caused Sestrin2 to associate with mTORC2, which was required for the increase in Sestrin2 protein stability and the reduction in mTORC1 activity...
July 18, 2017: Cell Reports
https://www.readbyqxmd.com/read/28711935/association-of-msin1-with-mtorc2-ras-and-akt-reveals-a-crucial-domain-on-msin1-involved-in-akt-phosphorylation
#3
Chien-An Yao, Sara Ortiz-Vega, Yun-Ya Sun, Chiang-Ting Chien, Jen-Hua Chuang, Yenshou Lin
mSin1 is a unique component within the mammalian target of rapamycin (mTOR) complex 2 (mTORC2), which is responsible for cellular morphology and glucose metabolism. The association between mSin1 and other mTORC2 components, as well as their functions, has been explored previously; nevertheless, the mapping of the various binding domains of the components is lacking. Based on an evolutionary analysis of the gene, we constructed various fragments and truncated-forms of mSin1. We characterized the individual binding sites of mSin1 with its various partners, including mTOR, Rictor, Ras, and Akt...
June 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28703798/mtorc2-regulates-hedgehog-pathway-activity-by-promoting-stability-to-gli2-protein-and-its-nuclear-translocation
#4
Samarpan Maiti, Susmita Mondal, Eswara M Satyavarapu, Chitra Mandal
mTORC2 is aberrantly activated in cancer and therefore is considered to be an important therapeutic target. The hedgehog pathway, which is also often hyperactivated, regulates transcription of several genes associated with angiogenesis, metastasis, cellular proliferation and cancer stem cell (CSC) regeneration. However, the contribution of mTORC2 toward hedgehog pathway activity has not been explored yet. Here we have addressed the molecular cross talk between mTORC2 and hedgehog pathway activities in the context of glioblastoma multiforme, a malignant brain tumor using as a model system...
July 13, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28701787/avian-reovirus-p17-and-%C3%AF-a-act-cooperatively-to-downregulate-akt-by-suppressing-mtorc2-and-cdk2-cyclin-a2-and-upregulating-proteasome-psmb6
#5
Wei-Ru Huang, Pei-I Chi, Hung-Chuan Chiu, Jue-Liang Hsu, Brent L Nielsen, Tsai-Ling Liao, Hung-Jen Liu
Although we have shown that avian reovirus (ARV) p17-mediated inhibition of Akt leads to induction of autophagy, the precise mechanisms remain largely unknown. This study has identified a specific mechanism by which ARV coordinately regulates the degradation of ribosomal proteins by p17-mediated activation of E3 ligase MDM2 that targets ribosomal proteins and by σA-mediated upregulation of proteasome PSMB6. In addition to downregulating ribosomal proteins, p17 reduces mTORC2 assembly and disrupts mTORC2-robosome association, both of which inactivate mTORC2 leading to inhibition of Akt phosphorylation at S473...
July 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28699701/rictor-regulates-the-vasculogenic-mimicry-of-melanoma-via-the-akt-mmp-2-9-pathway
#6
Xingmei Liang, Ran Sun, Xiulan Zhao, Yanhui Zhang, Qiang Gu, Xueyi Dong, Danfang Zhang, Junying Sun, Baocun Sun
Vasculogenic mimicry (VM)-positive melanomas are usually associated with poor prognosis. Rictor, the key component of the rapamycin-insensitive complex of mTOR (mTORC2), is up-regulated in several cancers, especially in melanomas with poor prognosis. The aim of this study was to investigate the role of Rictor in the regulation of VM and the mechanism underlying this possible regulation. VM channels were found in 35 of 81 tested melanoma samples and high Rictor expression correlated with VM structures. Moreover, Kaplan-Meier survival curves indicated that VM structures and high Rictor expression correlated with shorter survival in patients with melanoma...
July 12, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28694518/pdk1-plays-a-vital-role-on-hematopoietic-stem-cell-function
#7
Tianyuan Hu, Cong Li, Le Wang, Yingchi Zhang, Luyun Peng, Hui Cheng, Yajing Chu, Weili Wang, Hideo Ema, Yingdai Gao, Zhenyu Ju, Zhongzhou Yang, Xiaomin Wang, Tao Cheng, Weiping Yuan
3-Phosphoinositide-dependent protein kinase 1 (PDK1) is a pivotal regulator in the phosphoinositide 3-kinase (PI3K)-Akt signaling pathway that have been shown to play key roles in the functional development of B and T cells via activation of AGC protein kinases during hematopoiesis. However, the role of PDK1 in HSCs has not been fully defined. Here we specifically deleted the PDK1 gene in the hematopoietic system and found that PDK1-deficient HSCs exhibited impaired function and defective lineage commitment abilities...
July 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28692058/tumor-suppressor-pdcd4-attenuates-sin1-translation-to-inhibit-invasion-in-colon-carcinoma
#8
Q Wang, J Zhu, Y-W Wang, Y Dai, Y-L Wang, C Wang, J Liu, A Baker, N H Colburn, H-S Yang
Programmed cell death 4 (Pdcd4), a tumor invasion suppressor, is frequently downregulated in colorectal cancer and other cancers. In this study, we find that loss of Pdcd4 increases the activity of mammalian target of rapamycin complex 2 (mTORC2) and thereby upregulates Snail expression. Examining the components of mTORC2 showed that Pdcd4 knockdown increased the protein but not mRNA level of stress-activated-protein kinase interacting protein 1 (Sin1), which resulted from enhanced Sin1 translation. To understand how Pdcd4 regulates Sin1 translation, the SIN1 5' untranslated region (5'UTR) was fused with luciferase reporter and named as 5'Sin1-Luc...
July 10, 2017: Oncogene
https://www.readbyqxmd.com/read/28679058/pharmacological-inhibition-of-mtor-kinase-reverses-right-ventricle-remodeling-and-improves-right-ventricle-structure-and-function-in-rats
#9
Andressa Pena, Ahasanul Kobir, Dmitry Goncharov, Akiko Goda, Tatiana V Kudryashova, Arnab Ray, Rebecca Vanderpool, Jeffrey Baust, Baojun Chang, Ana L Mora, John Gorcsan Iii, Elena A Goncharova
Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling, increased pulmonary artery pressure (PAP), right heart afterload and death. Mechanistic target of rapamycin (mTOR) promotes smooth muscle cell proliferation, survival and pulmonary vascular remodeling via two functionally distinct complexes, mTORC1 (supports cell growth) and mTORC2 (promotes cell survival), and dual mTORC1/mTORC2 inhibition selectively induces PAH PAVSMC apoptosis and reverses pulmonary vascular remodeling...
July 5, 2017: American Journal of Respiratory Cell and Molecular Biology
https://www.readbyqxmd.com/read/28667005/mtorc2-regulates-the-cystine-glutamate-antiporter-xct
#10
(no author information available yet)
mTORC2 controls glutamate and glutathione metabolism in cancer cells by phosphorylating xCT.
June 30, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28666462/two-distinct-mtorc2-dependent-pathways-converge-on-rac1-to-drive-breast-cancer-metastasis
#11
Meghan Morrison Joly, Michelle M Williams, Donna J Hicks, Bayley Jones, Violeta Sanchez, Christian D Young, Dos D Sarbassov, William J Muller, Dana Brantley-Sieders, Rebecca S Cook
BACKGROUND: The importance of the mTOR complex 2 (mTORC2) signaling complex in tumor progression is becoming increasingly recognized. HER2-amplified breast cancers use Rictor/mTORC2 signaling to drive tumor formation, tumor cell survival and resistance to human epidermal growth factor receptor 2 (HER2)-targeted therapy. Cell motility, a key step in the metastatic process, can be activated by mTORC2 in luminal and triple negative breast cancer cell lines, but its role in promoting metastases from HER2-amplified breast cancers is not yet clear...
June 30, 2017: Breast Cancer Research: BCR
https://www.readbyqxmd.com/read/28659828/formal-modeling-of-mtor-associated-biological-regulatory-network-reveals-novel-therapeutic-strategy-for-the-treatment-of-cancer
#12
Zurah Bibi, Jamil Ahmad, Amnah Siddiqa, Rehan Z Paracha, Tariq Saeed, Amjad Ali, Hussnain Ahmed Janjua, Shakir Ullah, Emna Ben Abdallah, Olivier Roux
Cellular homeostasis is a continuous phenomenon that if compromised can lead to several disorders including cancer. There is a need to understand the dynamics of cellular proliferation to get deeper insights into the prevalence of cancer. Mechanistic Target of Rapamycin (mTOR) is implicated as the central regulator of the metabolic pathway involved in growth whereas its two distinct complexes mTORC1 and mTORC2 perform particular functions in cellular propagation. To date, mTORC1 is a well defined therapeutic target to inhibit uncontrolled cell division, while the role of mTORC2 is not well characterized...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28658303/critical-role-of-sik3-in-mediating-high-salt-and-il-17-synergy-leading-to-breast-cancer-cell-proliferation
#13
Suneetha Amara, Ciera Majors, Bipradas Roy, Salisha Hill, Kristie L Rose, Elbert L Myles, Venkataswarup Tiriveedhi
Chronic inflammation is a well-known precursor for cancer development and proliferation. We have recently demonstrated that high salt (NaCl) synergizes with sub-effective interleukin (IL)-17 to induce breast cancer cell proliferation. However, the exact molecular mechanisms mediating this effect are unclear. In our current study, we adopted a phosphoproteomic-based approach to identify salt modulated kinase-proteome specific molecular targets. The phosphoprotemics based binary comparison between heavy labelled MCF-7 cells treated with high salt (Δ0...
2017: PloS One
https://www.readbyqxmd.com/read/28650435/corrigendum-omega-3-polyunsaturated-fatty-acids-attenuate-fibroblast-activation-and-kidney-fibrosis-involving-mtorc2-signaling-suppression
#14
Zhifeng Zeng, Haiyuan Yang, Ying Wang, Jiafa Ren, Yifan Dai, Chunsun Dai
This corrects the article DOI: 10.1038/srep46146.
June 26, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28648777/mtorc2-regulates-amino-acid-metabolism-in-cancer-by-phosphorylation-of-the-cystine-glutamate-antiporter-xct
#15
Yuchao Gu, Claudio P Albuquerque, Daniel Braas, Wei Zhang, Genaro R Villa, Junfeng Bi, Shiro Ikegami, Kenta Masui, Beatrice Gini, Huijun Yang, Timothy C Gahman, Andrew K Shiau, Timothy F Cloughesy, Heather R Christofk, Huilin Zhou, Kun-Liang Guan, Paul S Mischel
Mutations in cancer reprogram amino acid metabolism to drive tumor growth, but the molecular mechanisms are not well understood. Using an unbiased proteomic screen, we identified mTORC2 as a critical regulator of amino acid metabolism in cancer via phosphorylation of the cystine-glutamate antiporter xCT. mTORC2 phosphorylates serine 26 at the cytosolic N terminus of xCT, inhibiting its activity. Genetic inhibition of mTORC2, or pharmacologic inhibition of the mammalian target of rapamycin (mTOR) kinase, promotes glutamate secretion, cystine uptake, and incorporation into glutathione, linking growth factor receptor signaling with amino acid uptake and utilization...
July 6, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28638048/maternal-folate-deficiency-causes-inhibition-of-mtor-signaling-down-regulation-of-placental-amino-acid-transporters-and-fetal-growth-restriction-in-mice
#16
Fredrick J Rosario, Peter W Nathanielsz, Theresa L Powell, Thomas Jansson
Maternal folate deficiency is linked to restricted fetal growth, however the underlying mechanisms remain to be established. Here we tested the hypothesis that mTOR functions as a folate sensor in vivo in mice and that maternal folate deficiency inhibits placental mTOR signaling and amino acid transporter activity and causes fetal growth restriction. Folate deficient mice had lower serum folate (-60%). In late pregnancy, fetal weight in the folate deficient group was decreased (-17%, p < 0.05), whereas placental weight, litter size and crown rump length were unaltered...
June 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28611306/erk-inhibition-sensitizes-cz415-induced-anti-osteosarcoma-activity-in-vitro-and-in-vivo
#17
Gang Yin, Jin Fan, Wei Zhou, Qingfeng Ding, Jun Zhang, Xuan Wu, Pengyu Tang, Hao Zhou, Bowen Wan, Guoyong Yin
mTOR is a valuable oncotarget for osteosarcoma. The anti-osteosarcoma activity by a novel mTOR kinase inhibitor, CZ415, was evaluated. We demonstrated that CZ415 potently inhibited survival and proliferation of known osteosarcoma cell lines (U2OS, MG-63 and SaOs2), and primary human osteosarcoma cells. Further, CZ415 provoked apoptosis and disrupted cell cycle progression in osteosarcoma cells. CZ415 treatment in osteosarcoma cells concurrently blocked mTORC1 and mTORC2 activation. Intriguingly, ERK-MAPK activation could be a major resistance factor of CZ415...
May 30, 2017: Oncotarget
https://www.readbyqxmd.com/read/28602697/gsk3-inhibitor-ar-a014418-promotes-osteogenic-differentiation-of-human-adipose-derived-stem-cells-via-erk-and-mtorc2-akt-signaling-pathway
#18
Min Zhang, Ping Zhang, Yunsong Liu, Yongsheng Zhou
Small molecule-based bone tissue engineering is emerging as a promising strategy for bone defects restoration. In this study, we intended to identify the roles and mechanisms of AR-A014418, a highly selective inhibitor of GSK3, on the osteogenic differentiation. We found that AR-A014418 exhibited a dose-dependent effect on osteogenic differentiation of human adipose-derived stem cells (hASCs). hASCs treated with AR-A014418 showed higher activity of ERK and mTORC2/Akt signaling. Administration of ERK inhibitor U0126 or knockdown of RICTOR by siRNA attenuated AR-A014418 induced osteogenic differentiation of hASCs...
August 19, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28600802/mtorc1-and-mtorc2-as-regulators-of-cell-metabolism-in-immunity
#19
REVIEW
Monika Linke, Stephanie Deborah Fritsch, Nyamdelger Sukhbaatar, Markus Hengstschläger, Thomas Weichhart
The mechanistic target of rapamycin (mTOR) pathway is an evolutionarily conserved signaling pathway that senses intra- and extracellular nutrients, growth factors, and pathogen-associated molecular patterns to regulate the function of innate and adaptive immune cell populations. In this Review, we focus on the role of the mTOR complex 1 (mTORC1) and mTORC2 in the regulation of the cellular energy metabolism of these immune cells to regulate and support immune responses. In this regard, mTORC1 and mTORC2 generally promote an anabolic response by stimulating protein synthesis, glycolysis, mitochondrial functions, and lipid synthesis to influence proliferation and survival, effector and memory responses, innate training and tolerance as well as hematopoietic stem cell maintenance and differentiation...
June 10, 2017: FEBS Letters
https://www.readbyqxmd.com/read/28592519/mechanistic-target-of-rapamycin-is-a-novel-molecular-mechanism-linking-folate-availability-and-cell-function
#20
REVIEW
Elena Silva, Fredrick J Rosario, Theresa L Powell, Thomas Jansson
Folate deficiency has been linked to a wide range of disorders, including cancer, neural tube defects, and fetal growth restriction. Folate regulates cellular function mediated by its involvement in the synthesis of nucleotides, which are needed for DNA synthesis, and its function as a methyl donor, which is critical for DNA methylation. Here we review current data showing that folate sensing by mechanistic target of rapamycin (mTOR) constitutes a novel and distinct pathway by which folate modulates cell functions such as nutrient transport, protein synthesis, and mitochondrial respiration...
July 2017: Journal of Nutrition
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