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Akt AND Doxycycline

Hui Chen, Xin-Yue Jing, Yu-Jun Shen, Tian-Lin Wang, Chen Ou, Sheng-Feng Lu, Yun Cai, Qian Li, Xia Chen, Ya-Juan Ding, Xiao-Chun Yu, Bing-Mei Zhu
Aims: To study the protective effects of late remote ischaemic preconditioning (RIPC) against myocardial ischaemia/reperfusion (I/R) injury and determine whether Stat5 is involved in this protection by using cardiomyocyte-specific Stat5 knockout mice (Stat5-cKO). Methods and results: Mice were exposed to lower limb RIPC or sham ischaemia. After 24 h, the left anterior descending artery (LAD) was ligated for 30 min, then reperfused for 180 min. The myocardial infarct size (IS), apoptotic rate of cardiomyocytes, and serum myocardial enzymes were measured to evaluate for cardioprotective effects...
April 1, 2018: Cardiovascular Research
Colin Kenny, Naomi McDonagh, Antonio Lazaro, Elaine O'Meara, Rut Klinger, Darran O'Connor, Fiona Roche, Karsten Hokamp, Maureen J O'Sullivan
The oncogenic mechanisms and tumour biology underpinning clear cell sarcoma of the kidney (CCSK), the second commonest paediatric renal malignancy, are poorly understood and currently, therapy depends heavily on doxorubicin with cardiotoxic side-effects. Previously, we characterized the balanced t(10;17)(q22;p13) chromosomal translocation, identified at that time as the only recurrent genetic aberration in CCSK. This translocation results in an in-frame fusion of the genes YWHAE (encoding 14-3-3ϵ) and NUTM2, with a somatic incidence of 12%...
March 2018: Journal of Pathology
Roberto Bellelli, Donata Vitagliano, Giorgia Federico, Pina Marotta, Anna Tamburrino, Paolo Salerno, Orlando Paciello, Serenella Papparella, Jeffrey A Knauf, James A Fagin, Samuel Refetoff, Giancarlo Troncone, Massimo Santoro
Here we describe a conditional doxycycline-dependent mouse model of RET/PTC3 (NCOA4-RET) oncogene-induced thyroid tumorigenesis. In these mice, after 10 days of doxycycline (dox) administration, RET/PTC3 expression induced mitogen activated protein kinase (MAPK) stimulation and a proliferative response which resulted in the formation of hyperplastic thyroid lesions. This was followed, after 2 months, by growth arrest accompanied by typical features of oncogene-induced senescence (OIS), including upregulation of p16INK4A and p21CIP, positivity at the Sudan black B, activation of the DNA damage response (DDR) markers γH2AX and pChk2 T68, and induction of p53 and p19ARF...
January 15, 2018: Molecular and Cellular Endocrinology
Maomao Yu, Cong Chen, Yini Cao, Rong Qi
The objective of this study was to investigate whether doxycycline (DOX) given at different doses and via different administration routes had protective or therapeutic effects on abdominal aortic aneurysm (AAA) induced by elastase in mice. Moreover, the anti-AAA mechanism of DOX was studied in TNF-α-stimulated vascular smooth muscle cell (VSMC) in vitro. For in vivo study, either daily administration of 30mg/kg of DOX by gavage or intraperitoneal injection of 15mg/kg DOX every other day for 14 days significantly prevented the development of AAA at its early stage...
September 15, 2017: European Journal of Pharmacology
S Sarkar, A Ghosh, S Banerjee, G Maity, A Das, M A Larson, V Gupta, I Haque, O Tawfik, S K Banerjee
CCN5/WISP-2 is an anti-invasive molecule and prevents breast cancer (BC) progression. However, it is not well understood how CCN5 prevents invasive phenotypes of BC cells. CCN5 protein expression is detected in estrogen receptor-α (ER-α) -positive normal breast epithelial cells as well as BC cells, which are weakly invasive and rarely metastasize depending on the functional status of ER-α. A unique molecular relation between CCN5 and ER-α has been established as the components of the same signaling pathway that coordinate some essential signals associated with the proliferation as well as delaying the disease progression from a non-invasive to invasive phenotypes...
May 22, 2017: Oncogenesis
Janani Panneerselvam, Akhil Srivastava, Ranganayaki Muralidharan, Qi Wang, Wei Zheng, Lichao Zhao, Alshine Chen, Yan D Zhao, Anupama Munshi, Rajagopal Ramesh
Interleukin (IL)-24, a novel tumor suppressor/cytokine exhibits antitumor activity against a broad-spectrum of human cancer cells. In a recent study, we showed that IL-24 inhibited AKT in lung cancer cells. However, the molecular mechanism of AKT inhibition by IL-24 remains elusive.The high mobility group (HMG) A1 a member of the non-histone chromosomal proteins and commonly referred to as architectural transcription factor, regulates transcription of various genes involved in cell growth and survival. Overexpression of HMGA1 has been shown to be associated with tumor progression and metastasis in several cancers, including human lung cancer...
October 25, 2016: Oncotarget
Elizabeth A Fry, Pankaj Taneja, Kazushi Inoue
The human c-ErbB2 (HER2) gene is amplified in ∼20% of human breast cancers (BCs), but the protein is overexpressed in ∼30% of the cases indicating that multiple different mechanisms contribute to HER2 overexpression in tumors. It has long been used as a molecular marker of BC for subcategorization for the prediction of prognosis and determination of therapeutic strategies. In comparison to ER(+) BCs, HER2-positive BCs are more invasive, but the patients respond to monoclonal antibody therapy with trastuzumab or tyrosine kinase inhibitors at least at early stages...
February 1, 2017: International Journal of Cancer. Journal International du Cancer
Young-Mi Lee, Saluja Kaduwal, Kug Hwa Lee, Jong-Chan Park, Woo-Jeong Jeong, Kang-Yell Choi
Sur8, a scaffold protein of the Ras pathway, interacts with Ras and Raf and modulates the Ras-extracellular signal-regulated kinase (ERK) pathway. Here we show that Sur8 is overexpressed in established human colorectal cancer (CRC) cell lines and CRC patient tissues. Moreover, Sur8 expression is increased during liver metastasis in CRC patients. Sur8 knockdown decreases ERK and Akt activities in CRC cell lines, regardless of their K-Ras, B-Raf or PI3K mutation status. Overexpression or knockdown of Sur8 increases or decreases, respectively, the proliferation or transformation of CRC cell lines...
July 29, 2016: Experimental & Molecular Medicine
Md Atiqur Rahman, Ali Salajegheh, Robert Anthony Smith, Alfred King-Yin Lam
The aim of our study was to inhibit BRAF kinase expression and investigate its effect on cellular functions in thyroid carcinomas. 8505C (BRAF (V600E/V600E)) undifferentiated thyroid carcinoma cell line and B-CPAP (BRAF (V600E/V600E)) papillary thyroid carcinoma cell line were used to develop doxycycline-inducible anti-BRAF shRNA stable cell lines. The inhibitions of BRAF expression in these cells were confirmed with qPCR and Western blot. Impacts of BRAF protein inhibition on cellular functions and signalling pathways were observed through Western blot, proliferation and colony formation assays...
October 2016: Endocrine
Abdelwahed Chtarto, Marie Humbert-Claude, Olivier Bockstael, Atze T Das, Sébastien Boutry, Ludivine S Breger, Bep Klaver, Catherine Melas, Pedro Barroso-Chinea, Tomas Gonzalez-Hernandez, Robert N Muller, Olivier DeWitte, Marc Levivier, Cecilia Lundberg, Ben Berkhout, Liliane Tenenbaum
Preclinical and clinical data stress the importance of pharmacologically-controlling glial cell line-derived neurotrophic factor (GDNF) intracerebral administration to treat PD. The main challenge is finding a combination of a genetic switch and a drug which, when administered at a clinically-approved dose, reaches the brain in sufficient amounts to induce a therapeutic effect. We describe a highly-sensitive doxycycline-inducible adeno-associated virus (AAV) vector. This vector allowed for the first time a longitudinal analysis of inducible transgene expression in the brain using bioluminescence imaging...
2016: Molecular Therapy. Methods & Clinical Development
Tsung-I Hsu, Yi-Chang Wang, Chia-Yang Hung, Chun-Hui Yu, Wu-Chou Su, Wen-Chang Chang, Jan-Jong Hung
The role of IL10 in the tumorigenesis of various cancer types is still controversial. Here, we found that increased IL10 levels are correlated with a poor prognosis in lung cancer patients. Moreover, IL10 levels were significantly increased in the lungs and serum of EGFRL858R- and Kras4bG12D-induced lung cancer mice, indicating that IL10 might facilitate lung cancer tumorigenesis. IL10 knockout in EGFRL858R and Kras4bG12D mice inhibited the development of lung tumors and decreased the levels of infiltrating M2 macrophages and tumor-promoting Treg lymphocytes...
April 12, 2016: Oncotarget
Marcia R Campbell, Hui Zhang, Shabnam Ziaee, Ana Ruiz-Saenz, Nathaniel Gulizia, Julie Oeffinger, Dhara N Amin, Deepika Ahuja, Mark M Moasser, Catherine C Park
The central role of HER2 as the disease driver and HER3 as its essential partner has made them rational targets for the treatment of HER2-amplifed breast cancers, and there is considerable interest in developing highly effective treatment regimens for this disease that consist of targeted therapies alone. Much of these efforts are focused on dual targeting approaches, particularly dual targeting of the HER2-HER3 tumor driver complex itself, or vertical combinations that target downstream PI3K or Akt in addition to HER2...
February 2016: Breast Cancer Research and Treatment
Toya M Albury-Warren, Veethika Pandey, Lina P Spinel, Michal M Masternak, Deborah A Altomare
Protein kinase B/AKT has three isoforms (AKT1-3) and is renowned for its central role in the regulation of cell growth and proliferation, due to its constitutive activation in various cancers. AKT2, which is highly expressed in insulin-responsive tissues, has been identified as a primary regulator of glucose metabolism as Akt2 knockout mice (Akt2(-/-)) are glucose-intolerant and insulin-resistant. However, the role of AKT1 in glucose metabolism is not as clearly defined. We previously showed that mice with myristoylated Akt1 (AKT1(Myr)) expressed through a bicistronic Pdx1-TetA and TetO-MyrAkt1 system were susceptible to islet cell carcinomas, and in this study we characterized an early onset, prediabetic phenotype...
January 2016: Journal of Endocrinology
Jingwen Huang, Wenru Su, Xiaoqing Chen, Xiaokang Cheng, Ye Dai, Longhui Han, Dan Liang
PURPOSE: We explored the anti-inflammatory effects of doxycycline in experimental uveitis and the underlying mechanisms. METHODS: Rats with endotoxin-induced uveitis (EIU) received doxycycline (1.5 mg/kg) or the control vehicle via intraperitoneal injection. Clinical scores were graded under a slit lamp. Rat peritoneal macrophages were used in vitro to further explore the anti-inflammatory mechanisms of doxycycline. The levels of nitric oxide (NO), TNF-α, IL-1β, prostaglandin E2 (PGE2), cyclooxygenase (COX)-2, I kappa B-α (IκB-α), inducible nitric oxide synthase (iNOS), Akt, caspase-3, and nuclear factor-kappa B (NF-κB) were analyzed...
October 2015: Investigative Ophthalmology & Visual Science
Travis J Cyphert, Robert T Morris, Lawrence M House, Tammy M Barnes, Yolanda F Otero, Whitney J Barham, Raphael P Hunt, Rinat Zaynagetdinov, Fiona E Yull, Timothy S Blackwell, Owen P McGuinness
Inflammatory lung diseases (e.g., pneumonia and acute respiratory distress syndrome) are associated with hyperglycemia, even in patients without a prior diagnosis of Type 2 diabetes. It is unknown whether the lung inflammation itself or the accompanying comorbidities contribute to the increased risk of hyperglycemia and insulin resistance. To investigate whether inflammatory signaling by airway epithelial cells can induce systemic insulin resistance, we used a line of doxycycline-inducible transgenic mice that express a constitutive activator of the NF-κB in airway epithelial cells...
November 1, 2015: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
Ho Yin Ng, Brian Gregory George Oliver, Janette Kay Burgess, Vera P Krymskaya, Judith Lee Black, Lyn M Moir
Lymphangioleiomyomatosis (LAM) is associated with dysfunction of the tuberous sclerosis complex (TSC) leading to enhanced cell proliferation and migration. This study aims to examine whether doxycycline, a tetracycline antibiotic, can inhibit the enhanced migration of TSC2-deficient cells, identify signalling pathways through which doxycycline works and to assess the effectiveness of combining doxycycline with rapamycin (mammalian target of rapamycin complex 1 inhibitor) in controlling cell migration, proliferation and wound closure...
November 2015: Journal of Cellular and Molecular Medicine
Janani Panneerselvam, Manish Shanker, Jiankang Jin, Cynthia D Branch, Ranganayaki Muralidharan, Yan D Zhao, Sunil Chada, Anupama Munshi, Rajagopal Ramesh
Interleukin (IL)-24 is a tumor suppressor/cytokine gene that undergoes post-translational modifications (PTMs). Glycosylation and ubiquitination are important for IL-24 protein stabilization and degradation respectively. Little is known about IL-24 protein phosphorylation and its role in IL-24-mediated anti-tumor activities. In this study we conducted molecular studies to determine whether IL-24 phosphorylation is important for IL-24-mediated anti-cancer activity.Human H1299 lung tumor cell line that was stably transfected with a doxycycline (DOX)-inducible (Tet-on) plasmid vector carrying the cDNA of IL-24-wild-type (IL-24wt) or IL-24 with all five phosphorylation sites replaced (IL-24mt) was used in the present study...
June 30, 2015: Oncotarget
George J Cerniglia, Souvik Dey, Shannon M Gallagher-Colombo, Natalie A Daurio, Stephen Tuttle, Theresa M Busch, Alexander Lin, Ramon Sun, Tatiana V Esipova, Sergei A Vinogradov, Nicholas Denko, Constantinos Koumenis, Amit Maity
Inhibition of the PI3K/Akt pathway decreases hypoxia within SQ20B human head and neck cancer xenografts. We set out to understand the molecular mechanism underlying this observation. We measured oxygen consumption using both a Clark electrode and an extracellular flux analyzer. We made these measurements after various pharmacologic and genetic manipulations. Pharmacologic inhibition of the PI3K/mTOR pathway or genetic inhibition of Akt/PI3K decreased the oxygen consumption rate (OCR) in vitro in SQ20B and other cell lines by 30% to 40%...
August 2015: Molecular Cancer Therapeutics
Changmei Liu, Fangmei Yang
Ovarian cancers present a mild clinical course when diagnosed early but an aggressive pathway when diagnosed in the peri- and postmenopausal periods. However, the predictability of tumor progression is stochastic and is difficult to predict. In the present study, we hypothesized to examine the key pathways that are dysregulated to promote epithelial-mesenchymal transition in serous ovarian carcinoma. Examination of these steps would help to identify ascitic fluid with cells poised for metastasis or otherwise...
September 2015: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Janani Panneerselvam, Jiankang Jin, Manish Shanker, Jason Lauderdale, Jonathan Bates, Qi Wang, Yan D Zhao, Stephen J Archibald, Timothy J Hubin, Rajagopal Ramesh
BACKGROUND: The stromal cell derived factor (SDF)-1/chemokine receptor (CXCR)-4 signaling pathway plays a key role in lung cancer metastasis and is molecular target for therapy. In the present study we investigated whether interleukin (IL)-24 can inhibit the SDF-1/CXCR4 axis and suppress lung cancer cell migration and invasion in vitro. Further, the efficacy of IL-24 in combination with CXCR4 antagonists was investigated. METHODS: Human H1299, A549, H460 and HCC827 lung cancer cell lines were used in the present study...
2015: PloS One
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