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https://www.readbyqxmd.com/read/28525892/rasal1-is-a-potent-regulator-of-hepatic-stellate-cell-activity-and-liver-fibrosis
#1
Akemi Takata, Motoyuki Otsuka, Takahiro Kishikawa, Mari Yamagami, Rei Ishibashi, Kazuma Sekiba, Tatsunori Suzuki, Motoko Ohno, Yui Yamashita, Takaya Abe, Ryota Masuzaki, Tsuneo Ikenoue, Kazuhiko Koike
Liver fibrosis, leading to cirrhosis and liver failure, can occur after chronic liver injury. The transition of hepatic stellate cells (HSCs) from quiescent cells into proliferative and fibrogenic cells is a central event in liver fibrosis. Here, we show that RAS protein activator like-1 (RASAL1), a RAS-GTPase-activating protein, which switches off RAS activity, is significantly decreased during HSC activation, and that HSC activation can be antagonized by forced expression of the RASAL1 protein. We demonstrate that RASAL1 suppresses HSC proliferation by regulating the Ras-MAPK pathway, and that RASAL1 suppresses HSC fibrogenic activity by regulating the PKA-LKB1-AMPK-SRF pathway by interacting with angiotensin II receptor, type 1...
May 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28522753/cyclin-d1-restrains-oncogene-induced-autophagy-by-regulating-the-ampk-lkb1-signaling-axis
#2
Mathew C Casimiro, Gabriele Di Sante, Agnese Di Rocco, Emanuele Loro, Claudia Pupo, Tim Pestell, Sara Bisetto, Marco A Velasco-Velàzquez, Xuanmao Jiao, Zhiping Li, Christine M Kusminski, Erin L Seifert, Chenguang Wang, Daniel Ly, Bin Zheng, Che-Hung Shen, Philipp E Scherer, Richard G Pestell
Autophagy activated after DNA damage or other stresses mitigates cellular damage by removing damaged proteins, lipids and organelles. Activation of the master metabolic kinase AMPK enhances autophagy. Here we report that cyclin D1 restrains autophagy by modulating the activation of AMPK. In cell models of human breast cancer or in a cyclinD1-deficient model, we observed a cyclin D1-mediated reduction in AMPK activation. Mechanistic investigations showed that Cyclin D1 inhibited mitochondrial function, promoted glycolysis and reduced activation of AMPK (pT172), possibly through a mechanism that involves cyclin D1-Cdk4/Cdk6 phosphorylation of LKB1...
May 18, 2017: Cancer Research
https://www.readbyqxmd.com/read/28514735/kif7-attenuates-prostate-tumor-growth-through-lkb1-mediated-akt-inhibition
#3
Kai Yau Wong, Jing Liu, Kwok Wah Chan
This study investigated kinesin family member 7 (KIF7) expression and function in prostate cancer (PCa). Our results showed that KIF7 was significantly downregulated in PCa, compared with normal, benign prostatic hyperplasia and prostate intraepithelial neoplasia tissues, partially through promoter hypermethylation. We further investigated the effects of KIF7 coiled coil (CC) domain and motor domain (MD) on PCa development in vitro and in vivo. Our results showed that KIF7-CC but not KIF7-MD significantly attenuated proliferation and colony formation, impeded migration and invasion, induced apoptosis and sensitized PCa cells to paclitaxel...
April 26, 2017: Oncotarget
https://www.readbyqxmd.com/read/28512260/targeting-metabolism-and-amp-activated-kinase-with-metformin-to-sensitize-non-small-cell-lung-cancer-nsclc-to-cytotoxic-therapy-translational-biology-and-rationale-for-current-clinical-trials
#4
REVIEW
Michael Troncone, Stephanie M Cargnelli, Linda A Villani, Naghmeh Isfahanian, Lindsay A Broadfield, Laura Zychla, Jim Wright, Gregory Pond, Gregory R Steinberg, Theodoros Tsakiridis
Lung cancer is the most fatal malignancy worldwide, in part, due to high resistance to cytotoxic therapy. There is need for effective chemo-radio-sensitizers in lung cancer. In recent years, we began to understand the modulation of metabolism in cancer and its importance in tumor progression and survival after cytotoxic therapy. The activity of biosynthetic pathways, driven by the Growth Factor Receptor/Ras/PI3k/Akt/mTOR pathway, is balanced by the energy stress sensor pathway of LKB1/AMPK/p53. AMPK responds both to metabolic and genotoxic stress...
April 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28507102/foxo3-pgc-1%C3%AE-signaling-axis-is-essential-for-cancer-stem-cell-properties-of-pancreatic-ductal-adenocarcinoma
#5
Motofumi Kumazoe, Mika Takai, Shun Hiroi, Chieri Takeuchi, Mai Kadomatsu, Takashi Nojiri, Hiroaki Onda, Jaehoon Bae, Yuhui Huang, Kanako Takamatsu, Shuya Yamashita, Kenji Kangawa, Hirofumi Tachibana
In 95% of patients with pancreatic ductal adenocarcinoma (PDAC), recurrence is observed following chemotherapy. Findings from several studies have indicated that cancer stem cells (CSCs) are resistant to anti-cancer agents and may be involved in cancer recurrence and metastasis. The CD44 protein is a major CSC marker, and CD44 also plays an indispensable role in the CSC properties in several cancers, including pancreatic cancer; however, no clinical approach exists to inhibit CD44 activity. Here, we have performed knockin/knock down experiments and we demonstrate that the forkhead box O3 (FOXO3)/liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK)/PPAR-γ co-activator-1β (PGC- 1β)/pyruvate dehydrogenase -A1 (PDHA1) pathway is essential for CD44 expression and CSC properties...
May 15, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28504720/a-clinical-drug-library-screen-identifies-clobetasol-propionate-as-an-nrf2-inhibitor-with-potential-therapeutic-efficacy-in-keap1-mutant-lung-cancer
#6
E-J Choi, B-J Jung, S-H Lee, H-S Yoo, E-A Shin, H-J Ko, S Chang, S-Y Kim, S-M Jeon
The Kelch-like ECH-associated protein 1 (KEAP1)-nuclear factor E2-related factor 2 (NRF2)pathway has a central role in cellular antioxidant defense. NRF2 activation due to KEAP1 or NRF2 mutations occurs frequently in many cancers, suggesting that NRF2 inhibition could be a promising therapeutic strategy. However, no potent NRF2 inhibitors are clinically available to date. To develop potent NRF2 inhibitors for therapeutic purpose, we screened ~4000 clinical compounds and determined clobetasol propionate (CP) as the most potent NRF2 inhibitor...
May 15, 2017: Oncogene
https://www.readbyqxmd.com/read/28500773/the-energy-sensing-lkb1-ampk%C3%AE-1-pathway-regulates-igf1-secretion-and-consequent-activation-of-the-igf1r-pkb-pathway-in-primary-hepatocytes
#7
Liang Chen, Qiaoli Chen, Ping Rong, Hong Yu Wang, Shuai Chen
The insulin-like growth factor 1 (IGF1) pathway has been linked with various diseases including diabetes, cancer and aging. In contrast to the well-established regulatory mechanisms controlling IGF1 expression, molecular mechanisms regulating of its secretion is not fully understood. The AMP-activated protein kinase (AMPK) is a key energy sensor, and accumulative evidence shows that AMPK is an attractive therapeutic target for treatment of diabetes, cancer and aging. Here we found that deficiency of AMPK promoted IGF1 secretion in mouse primary hepatocytes...
May 13, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28494245/global-reprogramming-of-host-kinase-signaling-in-response-to-fungal-infection
#8
Aseem Pandey, Sheng Li Ding, Qing-Ming Qin, Rahul Gupta, Gabriel Gomez, Furong Lin, Xuehuan Feng, Luciana Fachini da Costa, Sankar P Chaki, Madhu Katepalli, Elizabeth D Case, Erin J van Schaik, Tabasum Sidiq, Omar Khalaf, Angela Arenas, Koichi S Kobayashi, James E Samuel, Gonzalo M Rivera, Robert C Alaniz, Sing-Hoi Sze, Xiaoning Qian, William J Brown, Allison Rice-Ficht, William K Russell, Thomas A Ficht, Paul de Figueiredo
Cryptococcus neoformans (Cn) is a deadly fungal pathogen whose intracellular lifestyle is important for virulence. Host mechanisms controlling fungal phagocytosis and replication remain obscure. Here, we perform a global phosphoproteomic analysis of the host response to Cryptococcus infection. Our analysis reveals numerous and diverse host proteins that are differentially phosphorylated following fungal ingestion by macrophages, thereby indicating global reprogramming of host kinase signaling. Notably, phagocytosis of the pathogen activates the host autophagy initiation complex (AIC) and the upstream regulatory components LKB1 and AMPKα, which regulate autophagy induction through their kinase activities...
May 10, 2017: Cell Host & Microbe
https://www.readbyqxmd.com/read/28494141/metformin-induces-osteoblastic-differentiation-of-human-induced-pluripotent-stem-cell-derived-mesenchymal-stem-cells
#9
Ping Wang, Tao Ma, Dong Guo, Kevin Hu, Yan Shu, Hockin H K Xu, Abraham Schneider
Metformin, a first-line anti-diabetic drug used by millions of patients has been shown to have potential osteogenic properties. The present study was performed to test the hypothesis that clinically relevant doses of metformin promote the osteogenic differentiation and mineralization of induced Pluripotent Stem Cell-derived Mesenchymal Stem Cells (iPSC-MSCs). iPSC-MSCs were treated with metformin (10 μM) to assess cell viability, osteogenic differentiation, mineralization, and activation of the LKB1/AMP-activated protein kinase (AMPK) signaling pathway, a surrogate marker of metformin action...
May 11, 2017: Journal of Tissue Engineering and Regenerative Medicine
https://www.readbyqxmd.com/read/28493443/natural-alkaloid-bouchardatine-ameliorates-metabolic-disorders-in-high-fat-diet-fed-mice-via-stimulating-the-sirt1-lkb1-ampk-axis
#10
Yong Rao, Hong Yu, Lin Gao, Yu-Ting Lu, Zhao Xu, Hong Liu, Lian-Quan Gu, Ji-Ming Ye, Zhi-Shu Huang
BACKGROUND AND PURPOSE: Promoting energy metabolism is known to provide therapeutic effects for obesity and associated metabolic disorders. The present study evaluated the therapeutic effects of the newly-identified bouchardatine (Bou) on obesity associated metabolic disorders and the molechular mechanisms for these effects. EXPERIMENTAL APPROACH: The molecular mode of action of Bou for its effects on lipid metabolism was first examined in 3T3-L1 adipocytes and HepG2 cells...
May 10, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28492544/halofuginone-dually-regulates-autophagic-flux-through-nutrient-sensing-pathways-in-colorectal-cancer
#11
Guo-Qing Chen, Rui-Hong Gong, Da-Jian Yang, Ge Zhang, Ai-Ping Lu, Siu-Cheong Yan, Shu-Hai Lin, Zhao-Xiang Bian
Autophagy has a key role in metabolism and impacts on tumorigenesis. Our previous study found that halofuginone (HF) exerts anticancer activity in colorectal cancer (CRC) by downregulating Akt/mTORC1 (mechanistic target of rapamycin complex 1) signaling pathway. But whether and how HF regulates autophagy and metabolism to inhibit cancer growth remains an open question. Here, we unveil that HF activates ULK1 by downregulation of its phosphorylation site at Ser757 through Akt/mTORC1 signaling pathway, resulting in induction of autophagic flux under nutrient-rich condition...
May 11, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28483946/p53-maintains-baseline-expression-of-multiple-tumor-suppressor-genes
#12
Kyrie Pappas, Jia Xu, Sakellarios Zairis, Lois Resnick-Silverman, Francesco Abate, Nicole Steinbach, Sait Ozturk, Lao H Saal, Tao Su, Pamela Cheung, Hank Schmidt, Stuart A Aaronson, Hanina Hibshoosh, James J Manfredi, Raul Rabadan, Ramon Parsons
TP53 is the most commonly mutated tumor suppressor gene and its mutation drives tumorigenesis. Using ChIP-seq for p53 in the absence of acute cell stress, we found that wild-type but not mutant p53 binds and activates numerous tumor suppressor genes including PTEN, STK11(LKB1), miR-34a, KDM6A(UTX), FOXO1, PHLDA3, and TNFRSF10B through consensus binding sites in enhancers and promoters. Depletion of p53 reduced expression of these target genes, and analysis across 18 tumor types showed that mutation of TP53 associated with reduced expression of many of these genes...
May 8, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28473727/cryptolepine-inhibits-melanoma-cell-growth-through-coordinated-changes-in-mitochondrial-biogenesis-dynamics-and-metabolic-tumor-suppressor-ampk%C3%AE-1-2-lkb1
#13
Harish C Pal, Ram Prasad, Santosh K Katiyar
Dysregulated mitochondrial dynamics and biogenesis have been associated with various pathological conditions including cancers. Here, we assessed the therapeutic effect of cryptolepine, a pharmacologically active alkaloid derived from the roots of Cryptolepis sanguinolenta, on melanoma cell growth. Treatment of human melanoma cell lines (A375, Hs294t, SK-Mel28 and SK-Mel119) with cryptolepine (1.0, 2.5, 5.0 and 7.5 μM) for 24 and 48 h significantly (P < 0.001) inhibited the growth of melanoma cells but not normal melanocytes...
May 4, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28463229/comparative-oncogenomics-identifies-tyrosine-kinase-fes-as-a-tumor-suppressor-in-melanoma
#14
Michael Olvedy, Julie C Tisserand, Flavie Luciani, Bram Boeckx, Jasper Wouters, Sophie Lopez, Florian Rambow, Sara Aibar, Bernard Thienpont, Jasmine Barra, Corinna Köhler, Enrico Radaelli, Sophie Tartare-Deckert, Stein Aerts, Patrice Dubreuil, Joost J van den Oord, Diether Lambrechts, Paulo De Sepulveda, Jean-Christophe Marine
Identification and functional validation of oncogenic drivers are essential steps toward advancing cancer precision medicine. Here, we have presented a comprehensive analysis of the somatic genomic landscape of the widely used BRAFV600E- and NRASQ61K-driven mouse models of melanoma. By integrating the data with publically available genomic, epigenomic, and transcriptomic information from human clinical samples, we confirmed the importance of several genes and pathways previously implicated in human melanoma, including the tumor-suppressor genes phosphatase and tensin homolog (PTEN), cyclin dependent kinase inhibitor 2A (CDKN2A), LKB1, and others...
May 2, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28454310/downregulation-of-lkb1-promotes-tumor-progression-and-predicts-unfavorable-prognosis-in-patients-with-glioma
#15
Jiehao Huang, Hongwu Chen, Quantang Wei, Ziheng Zhang, Zhiwei Zhong, Yimin Xu
The liver kinase B1 (LKB1)/5'-adenosine monophosphate-activated protein kinase pathway has been reported to facilitate glioma cell growth by improving growth conditions. To investigate the clinical significance of LKB1 in human gliomas western blot analysis and quantitative polymerase chain reaction experiments were performed. The present study demonstrated that LKB1 expression was markedly decreased at the messenger RNA and protein levels in 30 freshly prepared glioma tissues, compared with non-neoplastic brain tissues (P<0...
March 2017: Oncology Letters
https://www.readbyqxmd.com/read/28451462/pulmonary-adenocarcinoma-with-mucin-production-modulates-phenotype-according-to-common-genetic-traits-a-reappraisal-of-mucinous-adenocarcinoma-and-colloid-adenocarcinoma
#16
Angelica Sonzogni, Fabrizio Bianchi, Alessandra Fabbri, Mara Cossa, Giulio Rossi, Alberto Cavazza, Elena Tamborini, Federica Perrone, Adele Busico, Iolanda Capone, Benedetta Picciani, Barbara Valeri, Ugo Pastorino, Giuseppe Pelosi
Whether invasive mucinous adenocarcinoma (IMA) and colloid adenocarcinoma (ICA) of the lung represent separate tumour entities, or simply lie within a spectrum of phenotypic variability, is worth investigating. Fifteen ICA, 12 IMA, 9 ALK-rearranged adenocarcinomas (ALKA), 8 non-mucinous KRAS-mutated adenocarcinomas (KRASA) and 9 mucinous breast adenocarcinomas (MBA) were assessed by immunohistochemistry for alveolar (TTF1, cytoplasmic MUC1), intestinal (CDX-2, MUC2), gastric (membrane MUC1, MUC6), bronchial (MUC5AC), mesenchymal (vimentin), neuroendocrine (chromogranin A, synaptophysin), sex steroid hormone-related (oestrogen and progesterone receptors), pan-mucinous (HNF4A) and pan-epithelial (keratin 7) lineage biomarkers and by targeted next generation sequencing (TNGS) for 50 recurrently altered cancer genes...
April 2017: Journal of Pathology. Clinical Research
https://www.readbyqxmd.com/read/28450156/microrna-7-impairs-autophagy-derived-pools-of-glucose-to-suppress-pancreatic-cancer-progression
#17
Dian-Na Gu, Ming-Jie Jiang, Zhu Mei, Juan-Juan Dai, Chen-Yun Dai, Chi Fang, Qian Huang, Ling Tian
Pancreatic cancer commonly addicts to aerobic glycolysis, and abnormally activates autophagy to adapt the stringent metabolic microenvironment. microRNA-7 (miR-7) was supposed to modulate various gastrointestinal cancer progression. We wonder whether miR-7 could destroy the reprogrammed metabolic homeostasis in pancreatic cancer via modulating the level of autophagy, and further affect tumor proliferation and survival. Herein, we first reported that pancreatic cancer could take advantage of autophagy as a survival strategy to provide essential glucose required for glycolysis metabolism...
April 25, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28435024/lkb1-deletion-in-murine-b-lymphocytes-promotes-cell-death-and-cancer
#18
George P Souroullas, Yuri Fedoriw, Louis M Staudt, Norman E Sharpless
LKB1 (aka STK11) is a potent tumor suppressor in solid tumors such as melanoma and lung adenocarcinoma, but inactivation in hematopoietic cells causes cell death, without signs of tumorigenesis. We noted somatic LKB1 deletion or mutation at low frequency in human B cell lymphoma. In order to determine if LKB1 inactivation is a passenger or driver event in lymphoid cancers, we examined the effects of conditional inactivation of Lkb1 in murine lymphocytes. Consistent with prior reports, Lkb1 deletion in either T or B cells resulted in massive, lineage-specific apoptosis...
April 20, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28410423/daf-18-pten-signals-through-aak-1-ampk-to-inhibit-mpk-1-mapk-in-feedback-control-of-germline-stem-cell-proliferation
#19
Patrick Narbonne, Paul S Maddox, Jean-Claude Labbé
Under replete growth conditions, abundant nutrient uptake leads to the systemic activation of insulin/IGF-1 signalling (IIS) and the promotion of stem cell growth/proliferation. Activated IIS can stimulate the ERK/MAPK pathway, the activation of which also supports optimal stem cell proliferation in various systems. Stem cell proliferation rates can further be locally refined to meet the resident tissue's need for differentiated progeny. We have recently shown that the accumulation of mature oocytes in the C...
April 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28409350/primary-cilia-in-cystic-kidney-disease
#20
Prachee Avasthi, Robin L Maser, Pamela V Tran
Primary cilia are small, antenna-like structures that detect mechanical and chemical cues and transduce extracellular signals. While mammalian primary cilia were first reported in the late 1800s, scientific interest in these sensory organelles has burgeoned since the beginning of the twenty-first century with recognition that primary cilia are essential to human health. Among the most common clinical manifestations of ciliary dysfunction are renal cysts. The molecular mechanisms underlying renal cystogenesis are complex, involving multiple aberrant cellular processes and signaling pathways, while initiating molecular events remain undefined...
2017: Results and Problems in Cell Differentiation
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