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Akt AND Doxycycline

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...
September 2, 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...
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
Ha-Na Na, Olga Dubuisson, Vijay Hegde, Jae-Hwan Nam, Nikhil V Dhurandhar
BACKGROUND: Aging and obesity are associated with elevated pro-inflammatory cytokines such as monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor (TNF)α, which are linked to insulin resistance. Anti-inflammatory agents have marginal effect in improving insulin resistance. Hence, agents are needed to improve glycemic control despite the inflammation. Ad36, a human adenovirus, increases TNFα and MCP1 mRNA in adipose tissue, yet improves glycemic control in mice. Ad36 via its E4orf1 gene, up-regulates AKT/glucose transporter (Glut)-4 signaling to enhance cellular glucose uptake...
May 2016: Biochimie
Longhui Han, Wenru Su, Jingwen Huang, Jingwen Zhou, Sujuan Qiu, Dan Liang
Lymphangiogenesis is significantly involved in the pathogenesis of diseases, including graft rejection, cancer metastasis and various inflammatory conditions. The inhibition of lymphangiogenesis has become a new therapeutic target for the treatment of these diseases. Here, we explored the anti-lymphangiogenic effects of doxycycline in inflammation-induced lymphangiogenesis (ILA) in the cornea and the underlying mechanisms. In the present study, mice with ILA of the cornea were treated with topical doxycycline (0...
2014: PloS One
Mi-Yoon Chang, Yong-Hee Rhee, Sang-Hoon Yi, Su-Jae Lee, Rae-Kwon Kim, Hyongbum Kim, Chang-Hwan Park, Sang-Hun Lee
We here report that doxycycline, an antibacterial agent, exerts dramatic effects on human embryonic stem and induced pluripotent stem cells (hESC/iPSCs) survival and self-renewal. The survival-promoting effect was also manifest in cultures of neural stem cells (NSCs) derived from hESC/iPSCs. These doxycycline effects are not associated with its antibacterial action, but mediated by direct activation of a PI3K-AKT intracellular signal. These findings indicate doxycycline as a useful supplement for stem cell cultures, facilitating their growth and maintenance...
August 12, 2014: Stem Cell Reports
Xiaoyong Fu, Chad J Creighton, Nrusingh C Biswal, Vijetha Kumar, Martin Shea, Sabrina Herrera, Alejandro Contreras, Carolina Gutierrez, Tao Wang, Sarmistha Nanda, Mario Giuliano, Gladys Morrison, Agostina Nardone, Kristen L Karlin, Thomas F Westbrook, Laura M Heiser, Pavana Anur, Paul Spellman, Sylvie M Guichard, Paul D Smith, Barry R Davies, Teresa Klinowska, Adrian V Lee, Gordon B Mills, Mothaffar F Rimawi, Susan G Hilsenbeck, Joe W Gray, Amit Joshi, C Kent Osborne, Rachel Schiff
INTRODUCTION: Activation of the phosphatidylinositol 3-kinase (PI3K) pathway in estrogen receptor α (ER)-positive breast cancer is associated with reduced ER expression and activity, luminal B subtype, and poor outcome. Phosphatase and tensin homolog (PTEN), a negative regulator of this pathway, is typically lost in ER-negative breast cancer. We set out to clarify the role of reduced PTEN levels in endocrine resistance, and to explore the combination of newly developed PI3K downstream kinase inhibitors to overcome this resistance...
September 11, 2014: Breast Cancer Research: BCR
Wenru Su, Qian Wan, Longhui Han, Jingwen Huang, Xiaoqing Chen, Guihua Chen, Song Guo Zheng, Dan Liang
Allergic diseases, which affect up to 20-30% of the world population, are still therapeutic challenge for allergists. Tetracyclines, which belong to an antibiotic drug family that possesses a striking variety of non-antibiotic properties, have been successfully applied to a wide range of diseases. However, their roles in allergic conjunctivitis and anaphylaxis and their underlying anti-allergy mechanisms remain elusive. Here, we reported that treatment with doxycycline significantly reduced IgE release from mouse B cells and the degranulation and inflammatory cytokines production of mouse mast cells (MCs) activated by IgE-dependent way...
October 1, 2014: Biochemical Pharmacology
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