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https://www.readbyqxmd.com/read/28212537/itraconazole-exerts-its-anti-melanoma-effect-by-suppressing-hedgehog-wnt-and-pi3k-mtor-signaling-pathways
#1
Guanzhao Liang, Musang Liu, Qiong Wang, Yongnian Shen, Huan Mei, Dongmei Li, Weida Liu
Malignant melanoma is the deadliest form of all skin cancers. Itraconazole, a commonly used systemic antifungal drug, has been tested for its anti-tumor effects on basal cell carcinoma, prostate cancer, and non-small cell lung cancer. Whether itraconazole has any specific anti-tumor effect on melanoma remains unknown. However, the goal of this study is to investigate the effect of itraconazole on melanoma and to reveal some details of its underlying mechanism. In the in vivo xenograft mouse model, we find that itraconazole can inhibit melanoma growth and extend the survival of melanoma xenograft mice, compared to non-itraconazole-treated mice...
February 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/28212321/therapeutic-approaches-targeting-myc-driven-prostate-cancer
#2
REVIEW
Richard J Rebello, Richard B Pearson, Ross D Hannan, Luc Furic
The transcript encoding the proto-oncogene MYC is commonly overexpressed in prostate cancer (PC). MYC protein abundance is also increased in the majority of cases of advanced and metastatic castrate-resistant PC (mCRPC). Accordingly, the MYC-directed transcriptional program directly contributes to PC by upregulating the expression of a number of pro-tumorigenic factors involved in cell growth and proliferation. A key cellular process downstream of MYC activity is the regulation of ribosome biogenesis which sustains tumor growth...
February 16, 2017: Genes
https://www.readbyqxmd.com/read/28211497/the-inflammatory-cytokine-tnf-%C3%AE-promotes-the-premature-senescence-of-rat-nucleus-pulposus-cells-via-the-pi3k-akt-signaling-pathway
#3
Pei Li, Yibo Gan, Yuan Xu, Lei Song, Liyuan Wang, Bin Ouyang, Chengmin Zhang, Qiang Zhou
Premature senescence of nucleus pulposus (NP) cells and inflammation are two common features of degenerated discs. This study investigated the effects of the inflammatory cytokine TNF-α on the premature senescence of NP cells and the molecular mechanism behind this process. Rat NP cells were cultured with or without different concentrations of TNF-α for 1 and 3 days. The inhibitor LY294002 was used to determine the role of the PI3K/Akt pathway. NP cells that were incubated with TNF-α for 3 days followed by 3 days of recovery in the control medium were used to analyze cellular senescence...
February 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28211035/resveratrol-decreases-foxo-protein-expression-through-pi3k-akt-dependent-pathway-inhibition-in-h2o2-treated-synoviocytes
#4
Bin Xu, Gaoyuan Wang, Junqiang Zhang, Wei Cao, Xiaoyu Chen
The aim of this study was to investigate the effects of resveratrol (Res) on hydrogen peroxide (H2O2)-treated fibroblast-like synoviocytes (FLSs) in vitro. We studied the phosphoinositide 3-kinase (PI3K)-Akt pathway inhibition-mediated effects of Res on forkhead box O (FoXO) mRNA expression levels. FLS viability was determined by Cell Counting Kit-8 (CCK-8) assay, and FLS apoptosis was measured by terminal deoxyribo nucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining and flow cytometry...
February 17, 2017: Histology and Histopathology
https://www.readbyqxmd.com/read/28210955/the-effects-of-igf-1-on-tnf-%C3%AE-treated-drg-neurons-by-modulating-atf3-and-gap-43-expression-via-pi3k-akt-s6k-signaling-pathway
#5
Lei Zhang, Yaping Yue, Meishuo Ouyang, Huaxiang Liu, Zhenzhong Li
Upregulation of the pro-inflammatory cytokine tumor necrosis factor α (TNF-α) is involved in the development and progression of numerous neurological disorders. Recent reports have challenged the concept that TNF-α exhibits only deleterious effects of pro-inflammatory destruction, and have raised the awareness that it may play a beneficial role in neuronal growth and function in particular conditions, which prompts us to further investigate the role of this cytokine. Insulin-like growth factor-1 (IGF-1) is a cytokine possessing powerful neuroprotective effects in promoting neuronal survival, neuronal differentiation, neurite elongation, and neurite regeneration...
February 16, 2017: Neurochemical Research
https://www.readbyqxmd.com/read/28210865/the-impact-of-melanoma-genetics-on-treatment-response-and-resistance-in-clinical-and-experimental-studies
#6
M Kunz, M Hölzel
Recent attempts to characterize the melanoma mutational landscape using high-throughput sequencing technologies have identified new genes and pathways involved in the molecular pathogenesis of melanoma. Apart from mutated BRAF, NRAS, and KIT, a series of new recurrently mutated candidate genes with impact on signaling pathways have been identified such as NF1, PTEN, IDH1, RAC1, ARID2, and TP53. Under targeted treatment using BRAF and MEK1/2 inhibitors either alone or in combination, a majority of patients experience recurrences, which are due to different genetic mechanisms such as gene amplifications of BRAF or NRAS, MEK1/2 and PI3K mutations...
February 16, 2017: Cancer Metastasis Reviews
https://www.readbyqxmd.com/read/28209725/soluble-trem2-induces-inflammatory-responses-and-enhances-microglial-survival
#7
Li Zhong, Xiao-Fen Chen, Tingting Wang, Zhe Wang, Chunyan Liao, Zongqi Wang, Ruizhi Huang, Daxin Wang, Xinxiu Li, Linbei Wu, Lin Jia, Honghua Zheng, Meghan Painter, Yuka Atagi, Chia-Chen Liu, Yun-Wu Zhang, John D Fryer, Huaxi Xu, Guojun Bu
Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor expressed in microglia in the brain. A soluble form of TREM2 (sTREM2) derived from proteolytic cleavage of the cell surface receptor is increased in the preclinical stages of AD and positively correlates with the amounts of total and phosphorylated tau in the cerebrospinal fluid. However, the physiological and pathological functions of sTREM2 remain unknown. Here, we show that sTREM2 promotes microglial survival in a PI3K/Akt-dependent manner and stimulates the production of inflammatory cytokines depending on NF-κB...
February 16, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28209720/acquired-expression-of-cbl-q367p-in-mice-induces-dysplastic-myelopoiesis-mimicking-chronic-myelomonocytic-leukemia
#8
Yuichiro Nakata, Takeshi Ueda, Akiko Nagamachi, Norimasa Yamasaki, Ken-Ichiro Ikeda, Yasuyuki Sera, Keiyo Takubo, Akinori Kanai, Hideaki Oda, Masashi Sanada, Seishi Ogawa, Kohichiro Tsuji, Yasuhiro Ebihara, Linda Wolff, Zen-Ichiro Honda, Toshio Suda, Toshiya Inaba, Hiroaki Honda
Chronic myelomonocytic leukemia (CMML) is a hematological malignancy characterized by uncontrolled proliferation of dysplastic myelomonocytes and frequent progression to acute myeloid leukemia (AML). We identified mutations in the Cbl gene, which encodes a negative regulator of cytokine signaling, in a subset of CMML patients. To investigate the contribution of mutant Cbl in CMML pathogenesis, we generated conditional knock-in mice for Cbl that express wild-type Cbl in a steady state and inducibly express Cbl(Q367P) , a CMML-associated Cbl mutant...
February 16, 2017: Blood
https://www.readbyqxmd.com/read/28209713/mir-718-represses-pro-inflammatory-cytokine-production-through-targeting-pten
#9
Parisa Kalantari, Omid F Harandi, Sarika Agarwal, Florentina Rus, Evelyn A Kurt-Jones, Katherine A Fitzgerald, Daniel R Caffrey, Douglas T Golenbock
Bacterial sepsis involves a complex interaction between the host immune response and bacterial lipopolysaccharides (LPS). LPS binds Toll-like receptor (TLR) 4, which leads to the release of pro-inflammatory cytokines that are essential for a potent innate immune response against pathogens. The innate immune system is tightly regulated as excessive inflammation can lead to organ failure and death. MicroRNAs have recently emerged as important regulators of the innate immune system. Here, we determined the function of miR-718, which is conserved across mammals and overlaps with the 5 UTR of the Interleukin-1 Receptor-Associated Kinase (IRAK1) gene...
February 16, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28209617/loss-of-ndrg2-expression-confers-oral-squamous-cell-carcinoma-with-enhanced-metastatic-potential
#10
Tomohiro Tamura, Tomonaga Ichikawa, Shingo Nakahata, Yudai Kondo, Yuri Tagawa, Kouji Yamamoto, Kentaro Nagai, Takashi Baba, Ryoji Yamaguchi, Mitsuru Futakuchi, Yoshihiro Yamashita, Kazuhiro Morishita
Loss of the tumor suppressor NDRG2 has been implicated in the development of oral squamous cell carcinoma (OSCC), acting by modulating PI3K/AKT-mediated dephosphorylation of PTEN at S380/S382/T383 (STT). Here we show that the majority of OSCC tumors with lymph node metastasis, a major prognostic factor, exhibit high levels of phosphorylated AKT-S473 and PTEN-STT and low levels of NDRG2 expression. In Ndrg2-deficient mice, which develop a wide range of tumors, we developed a model of OSCC by treatment with the tobacco surrogate 4-nitroquinoline-1-oxide (4-NQO)...
February 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28209487/lipoxin-a4-suppresses-osteoclastogenesis-in-raw264-7-cells-and-prevents-ovariectomy-induced-bone-loss
#11
Changyu Liu, Hanfeng Guan, Cong Cai, Feng Li, Jun Xiao
Lipoxin A4 (LXA4; 5S, 6R, 15Strihydroxy- 7,9,13-trans-11-eicosatetraenoic acid) is a metabolic product of arachidonic acid under the action of lipoxidase. This lipid molecule plays important roles in several biological functions, especially inflammatory processes. In vivo, LXA4 regulates the inflammatory response through several signaling pathways. Its mechanism suggests that it might have an effect on osteoclastogenesis and bone loss. Using both in vitro and in vivo studies, it was here observed that LXA4 could significantly inhibit the formation and function of osteoclasts and these effects could be blocked by Boc-2, the specific inhibitor of FPR2/ALX (the receptor of LXA4)...
February 13, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/28209091/hgf-induced-dna-synthesis-in-hepatocytes-is-suppressed-by-p38
#12
Monica Aasrum, Ingvild J Brusevold, Thoralf Christoffersen, G Hege Thoresen
Previous studies in rat hepatocytes have shown that the MEK/ERK, PI3K/Akt and p38 pathways are all involved in the activation of DNA synthesis by EGF and that sustained activation of MEK/ERK is required. Here, we show that although HGF stimulated DNA synthesis and activated signaling in the same manner as EGF, the contribution of the signaling pathways to the induction of DNA synthesis differed. While HGF-induced DNA synthesis was dependent on MEK/ERK, with no significant contribution from PI3K/Akt, p38 suppressed HGF-induced DNA synthesis...
December 2016: Growth Factors
https://www.readbyqxmd.com/read/28208754/gypenoside-xvii-prevents-atherosclerosis-by-attenuating-endothelial-apoptosis-and-oxidative-stress-insight-into-the-er%C3%AE-mediated-pi3k-akt-pathway
#13
Ke Yang, Haijing Zhang, Yun Luo, Jingyi Zhang, Min Wang, Ping Liao, Li Cao, Peng Guo, Guibo Sun, Xiaobo Sun
Phytoestrogens are estrogen-like compounds of plant origin. The pharmacological activities of phytoestrogens are predominantly due to their antioxidant, anti-inflammatory and lipid-lowering properties, which are mediated via the estrogen receptors (ERs): estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) and possibly G protein-coupled estrogen receptor 1 (GPER). Gypenoside XVII (GP-17) is a phytoestrogen that is widely used to prevent cardiovascular disease, including atherosclerosis, but the mechanism underlying these therapeutic effects is largely unclear...
February 9, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28207189/effects-of-human-mesenchymal-stem-cells-co-culture-on-calcium-induced-differentiation-of-normal-human-keratinocytes
#14
Shyam Kishor Sah, Hae Young Kim, Ji Hae Lee, Seong-Wook Lee, Hyung-Sik Kim, Yeon-Soo Kim, Kyung-Sun Kang, Tae-Yoon Kim
The influence of mesenchymal stem cells (MSCs) on keratinocytes in altered microenvironments is poorly understood. Here, we co-cultured umbilical cord blood-derived MSCs with normal human epidermal keratinocytes (NHEK) to evaluate their paracrine effect in the presence of high extracellular calcium (Ca(2+) ) concentration. High Ca(2+) environment to keratinocytes can disrupt normal skin barrier function due to abnormal/premature differentiation of keratinocytes. Surprisingly, we found that MSCs suppress both proliferation and differentiation of keratinocytes under a high Ca(2+) environment in TGFβ1-dependent manner...
February 16, 2017: Stem Cells
https://www.readbyqxmd.com/read/28205653/phosphorylation-of-zinc-channel-zip7-drives-mapk-pi3k-and-mtor-growth-and-proliferation-signalling
#15
T Nimmanon, S Ziliotto, S Morris, L Flanagan, K M Taylor
Zinc is an essential trace element participating in diverse biological processes. Cellular zinc levels are strictly controlled by two families of transport proteins: ZIP channels (SLC39A) and ZnT transporters (SLC30A). ZIP channels increase cytosolic zinc levels by importing zinc into cells or releasing zinc from intracellular stores such as the ER. Among all the 14 human members of the ZIP family, ZIP7 is a gatekeeper of zinc release from intracellular stores, requiring post-translational activation by phosphorylation on residues S275 and S276, resulting in activation of multiple downstream pathways...
February 16, 2017: Metallomics: Integrated Biometal Science
https://www.readbyqxmd.com/read/28205613/pak4-interacts-with-p85-alpha-implications-for-pancreatic-cancer-cell-migration
#16
Helen King, Kiruthikah Thillai, Andrew Whale, Prabhu Arumugam, Hesham Eldaly, Hemant M Kocher, Claire M Wells
It has been reported that p21-activated kinase 4 (PAK4) is amplified in pancreatic cancer tissue. PAK4 is a member of the PAK family of serine/threonine kinases, which act as effectors for several small GTPases, and has been specifically identified to function downstream of HGF-mediated c-Met activation in a PI3K dependent manner. However, the functionality of PAK4 in pancreatic cancer and the contribution made by HGF signalling to pancreatic cancer cell motility remain to be elucidated. We now find that elevated PAK4 expression is coincident with increased expression levels of c-Met and the p85α subunit of PI3K...
February 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28205079/magnesium-ions-promote-the-biological-behaviour-of-rat-calvarial-osteoblasts-by-activating-the-pi3k-akt-signalling-pathway
#17
Jian Wang, Xiang-Yu Ma, Ya-Fei Feng, Zhen-Sheng Ma, Tian-Cheng Ma, Yang Zhang, Xiang Li, Lin Wang, Wei Lei
Magnesium has been investigated as a biodegradable metallic material. Increased concentrations of Mg(2+) around magnesium implants due to biodegradation contribute to its satisfactory osteogenic capacity. However, the mechanisms underlying this process remain elusive. We propose that activation of the PI3K/Akt signalling pathway plays a role in the Mg(2+)-enhanced biological behaviours of osteoblasts. To test this hypothesis, 6, 10 and 18 mM Mg(2+) was used to evaluate the stimulatory effect of Mg(2+) on osteogenesis, which was assessed by evaluating cell adhesion, cell viability, ALP activity, extracellular matrix mineralisation and RT-PCR...
February 15, 2017: Biological Trace Element Research
https://www.readbyqxmd.com/read/28203054/uveal-melanoma-epidemiology-etiology-and-treatment-of-primary-disease
#18
REVIEW
Benjamin A Krantz, Nikita Dave, Kimberly M Komatsubara, Brian P Marr, Richard D Carvajal
Uveal melanoma (UM) is the most common intraocular malignancy and arises from melanocytes in the iris, ciliary body, or choroid. Early diagnosis and local treatment is crucial, as survival correlates with primary tumor size. However, approximately 50% of patients will develop metastatic disease with 6-12 months' survival from metastatic diagnosis. Genomic analyses have led to the development of gene-expression profiles that effectively predict metastatic progression; unfortunately, no adjuvant therapy has been shown to prolong survival to date...
2017: Clinical Ophthalmology
https://www.readbyqxmd.com/read/28202507/yap-taz-mediated-upregulation-of-gab2-leads-to-increased-sensitivity-to-growth-factor-induced-activation-of-the-pi3k-pathway
#19
Chao Wang, Chao Gu, Kang Jin Jeong, Dong Zhang, Wei Guo, Yiling Lu, Zhenlin Ju, Nattapon Panupinthu, Ji Yeon Yang, Mihai Gagea, Patrick Kwok Shing Ng, Fan Zhang, Gordon B Mills
The transcription regulators YAP and TAZ function as effectors of the HIPPO signaling cascade, critical for organismal development, cell growth, and cellular reprogramming, and YAP/TAZ is commonly misregulated in human cancers. The precise mechanism by which aberrant YAP/TAZ promotes tumor growth remains unclear. The HIPPO tumor suppressor pathway phosphorylates YAP and TAZ resulting in cytosolic sequestration with subsequent degradation. Here we report that the phosphatidylinositol 3' kinase (PI3K)/AKT pathway, which is critically involved in the pathophysiology of endometrial cancer (EC), interacts with the HIPPO pathway at multiple levels...
February 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28202458/sensitivity-to-pi3k-and-akt-inhibitors-is-mediated-by-divergent-molecular-mechanisms-in-subtypes-of-dlbcl
#20
Tabea Erdmann, Pavel Klener, James T Lynch, Michael Grau, Petra Vočková, Jan Molinsky, Diana Tuskova, Kevin Hudson, Urszula M Polanska, Michael Grondine, Michele Mayo, Beiying Dai, Matthias Pfeifer, Kristian Erdmann, Daniela Schwammbach, Myroslav Zapukhlyak, Annette M Staiger, German Ott, Wolfgang E Berdel, Barry R Davies, Francisco Cruzalegui, Marek Trneny, Peter Lenz, Simon T Barry, Georg Lenz
Activated B-cell-like (ABC) and germinal center B-cell-like (GCB) diffuse large B-cell lymphoma (DLBCL) represent the two major molecular DLBCL subtypes. They are characterized by differences in clinical course and by divergent addiction to oncogenic pathways. To determine activity of novel compounds in these two subtypes, we conducted an unbiased pharmacologic in vitro screen. The phosphatidylinositol-3-kinase (PI3K) alpha/delta (PI3Kα/δ) inhibitor AZD8835 showed marked potency in ABC DLBCL models, whereas the protein kinase B (AKT) inhibitor AZD5363 induced apoptosis in PTEN-deficient DLBCLs irrespective of their molecular subtype...
February 15, 2017: Blood
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