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Joanna Kopecka, Gregory M Rankin, Iris C Salaroglio, Sally-Ann Poulsen, Chiara Riganti
Carbonic anhydrase XII (CAXII) is a membrane enzyme that maintains pH homeostasis and sustains optimum P-glycoprotein (Pgp) efflux activity in cancer cells. Here, we investigated a panel of eight CAXII inhibitors (compounds 1-8), for their potential to reverse Pgp mediated tumor cell chemoresistance. Inhibitors (5 nM) were screened in human and murine cancer cells (colon, lung, breast, bone) with different expression levels of CAXII and Pgp. We identified three CAXII inhibitors (compounds 1, 2 and 4) that significantly (≥ 2 fold) increased the intracellular retention of the Pgp-substrate and chemotherapeutic doxorubicin, and restored its cytotoxic activity...
November 3, 2016: Oncotarget
Kamini Marathe, Nevin McVicar, Alex Li, Miranda Bellyou, Susan Meakin, Robert Bartha
Reversal of the intracellular/extracellular pH gradient is a hallmark of malignant tumors and is an important consideration in evaluating tumor growth potential and the effectiveness of anticancer therapies. Glioblastoma multiforme (GBM) brain tumors have increased expression of the carbonic anhydrase (CA) isozymes CAII, CAIX and CAXII that contribute to the altered regulation of intracellular pH (pHi). The anti-epileptic drug topiramate (TPM) inhibits CA action and may acidify the tumor intracellular compartment...
September 9, 2016: Journal of Neuro-oncology
Paul C McDonald, Shawn C Chafe, Shoukat Dedhar
Hypoxia is an important contributor to the heterogeneity of the microenvironment of solid tumors and is a significant environmental stressor that drives adaptations which are essential for the survival and metastatic capabilities of tumor cells. Critical adaptive mechanisms include altered metabolism, pH regulation, epithelial-mesenchymal transition, angiogenesis, migration/invasion, diminished response to immune cells and resistance to chemotherapy and radiation therapy. In particular, pH regulation by hypoxic tumor cells, through the modulation of cell surface molecules such as extracellular carbonic anhydrases (CAIX and CAXII) and monocarboxylate transporters (MCT-1 and MCT-4) functions to increase cancer cell survival and enhance cell invasion while also contributing to immune evasion...
2016: Frontiers in Cell and Developmental Biology
Mark C Lloyd, Jessica J Cunningham, Marilyn M Bui, Robert J Gillies, Joel S Brown, Robert A Gatenby
Spatial heterogeneity in tumors is generally thought to result from branching clonal evolution driven by random mutations that accumulate during tumor development. However, this concept rests on the implicit assumption that cancer cells never evolve to a fitness maximum because they can always acquire mutations that increase proliferative capacity. In this study, we investigated the validity of this assumption. Using evolutionary game theory, we demonstrate that local cancer cell populations will rapidly converge to the fittest phenotype given a stable environment...
June 1, 2016: Cancer Research
Kulthida Vaeteewoottacharn, Ryusho Kariya, Paweena Dana, Sawako Fujikawa, Kouki Matsuda, Koichi Ohkuma, Eriko Kudo, Ratthaphol Kraiklang, Chaisiri Wongkham, Sopit Wongkham, Seiji Okada
Cholangiocarcinoma (CCA) is a unique liver cancer subtype with an increasing incidence globally. The lack of specific symptoms and definite diagnostic markers results in a delayed diagnosis and disease progression. Systemic chemotherapy is commonly selected for advanced CCA even though its advantages remain unknown. Targeted therapy, especially anti-vascular endothelial growth factor (VEGF) therapy, is promising for CCA; however, improvements in the therapeutic regimen are necessary to overcome subsequent resistance...
July 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Narges K Tafreshi, Mark C Lloyd, Joshua B Proemsey, Marilyn M Bui, Jongphil Kim, Robert J Gillies, David L Morse
PURPOSE: Hypoxia is commonly observed in regions of primary tumors and metastases, and is associated with resistance to treatment, more aggressive tumor phenotypes and poor prognosis. Reliable and validated imaging biomarkers of hypoxia are needed for pre-clinical studies and clinical use. Expression of cell-surface carbonic anhydrases IX and XII (CAIX and CAXII) in tumor cells has been associated with tumor hypoxia. CAIX and CAXII specific antibodies conjugated to fluorescent dye were evaluated for the non-invasive detection of hypoxia in vivo...
April 2016: Molecular Imaging and Biology: MIB: the Official Publication of the Academy of Molecular Imaging
Rihab Bouchareb, Nancy Côté, Marie-Chloé-Boulanger, Khai Le Quang, Diala El Husseini, Jérémie Asselin, Fayez Hadji, Dominic Lachance, Elnur Elyar Shayhidin, Ablajan Mahmut, Philippe Pibarot, Yohan Bossé, Younes Messaddeq, Denis Boudreau, André Marette, Patrick Mathieu
AIMS: Calcific aortic valve stenosis (CAVS) is the most common heart valve disease. In the present work we sought to determine the reversibility of mineralization in the aortic valve. METHODS AND RESULTS: By using in vitro analyses we found that valve interstitial cells (VICs) have the ability to resorb minerals. We documented that agonist of P2Y2 receptor (P2Y2R) promoted the expression of carbonic anhydrase XII (CAXII) at the cell membrane of VICs, whereby minerals are resorbed...
May 2015: Journal of Molecular and Cellular Cardiology
Joanna Kopecka, Ivana Campia, Andrea Jacobs, Andreas P Frei, Dario Ghigo, Bernd Wollscheid, Chiara Riganti
Multidrug resistance (MDR) in cancer cells is a challenging phenomenon often associated with P-glycoprotein (Pgp) surface expression. Finding new ways to bypass Pgp-mediated MDR still remains a daunting challenge towards the successful treatment of malignant neoplasms such as colorectal cancer.We applied the Cell Surface Capture technology to chemosensitive and chemoresistant human colon cancer to explore the cell surface proteome of Pgp-expressing cells in a discovery-driven fashion. Comparative quantitative analysis of identified cell surface glycoproteins revealed carbonic anhydrase type XII (CAXII) to be up-regulated on the surface of chemoresistant cells, similarly to Pgp...
March 30, 2015: Oncotarget
Martina Takacova, Petra Bullova, Veronika Simko, Lucia Skvarkova, Martina Poturnajova, Lucia Feketeova, Pavel Babal, Antti J Kivela, Teijo Kuopio, Juraj Kopacek, Jaromir Pastorek, Seppo Parkkila, Silvia Pastorekova
Medullary thyroid carcinoma is a relatively rare tumor with poor prognosis and therapy response. Its phenotype is determined by both genetic alterations (activating RET oncoprotein) and physiological stresses, namely hypoxia [activating hypoxia-inducible factor (HIF)]. Here, we investigated the cooperation between these two mechanisms. The idea emerged from the immunohistochemical analysis of carbonic anhydrases (CA) IX and XII expression in thyroid cancer. Although CAXII was present in all types of thyroid carcinomas, CAIX, a direct HIF target implicated in tumor progression, was associated with aggressive medullary and anaplastic carcinomas, and its expression pattern in medullary thyroid carcinomas suggested contribution of both hypoxic and oncogenic signaling...
April 2014: American Journal of Pathology
Marius Ilie, Véronique Hofman, Joséphine Zangari, Johanna Chiche, Jérôme Mouroux, Nathalie M Mazure, Jacques Pouysségur, Patrick Brest, Paul Hofman
The disorganized neo-vasculature in tumours causes fluctuations in the concentration of oxygen, which contributes to tumour development and metastatic potential. Although hypoxic regulation of the expression of the carbonic anhydrases CAIX and CAXII is well established, the effect of re-oxygenation on these proteins remains to be elucidated. A549 and H1975 human lung cancer cell lines were exposed to hypoxia for 24 h and then re-oxygenated. CAIX or CAXII expression and cell cycle progression at different time-points were monitored...
October 2013: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Marius I Ilie, Sandra Lassalle, Elodie Long-Mira, Véronique Hofman, Joséphine Zangari, Gilles Bénaim, Alexandre Bozec, Nicolas Guevara, Juliette Haudebourg, Isabelle Birtwisle-Peyrottes, José Santini, Patrick Brest, Paul Hofman
BRAF (V600E) causes upregulation of tissue inhibitor of metalloproteinase-1 (TIMP-1), which promotes cell invasion in papillary thyroid carcinoma (PTC). Hypoxia-inducible factor-1α (HIF- α) is regulated by hypoxia and also by the BRAF-mediated signaling pathway in PTC. We assessed the association of expression of TIMP-1, HIF-1α, and hypoxia-inducible carbonic anhydrase IX (CAIX) and XII (CAXII) with clinical parameters in PTC. TPC-1/BRAF (WT) wild-type and BcPAP/BRAF (V600E) -mutated PTC cell lines were selected to study the effects of the BRAF (V600E) mutation and hypoxia on expression in vitro of TIMP-1, CAIX, and CAXII proteins by immunoblotting...
September 2013: Virchows Archiv: An International Journal of Pathology
Khadijeh Gholami, Sekaran Muniandy, Naguib Salleh
UNLABELLED: Precise control of uterine fluid pH, volume and electrolytes is important for the reproductive processes. In this study, we examined the functional involvement of multiple proteins including Cystic Fibrosis Transmembrane Regulator (CFTR), Cl(-)/HCO3 (-) exchanger (SLC26A6), sodium-hydrogen exchanger-1 (NHE-1) and carbonic anhydrase (CA) in the regulation of these uterine fluid parameters. METHODS: Adult female WKY rats were divided into intact, non-ovariectomised at different oestrous cycle phases and ovariectomised treated with sex-steroids...
2013: International Journal of Medical Sciences
Jeroen F Vermeulen, Elsken van der Wall, Arjen J Witkamp, Paul J van Diest
PURPOSE: Achieving radicality during breast conserving surgery for pure ductal carcinoma in situ (DCIS) of the breast and invasive cancer surrounded by DCIS is challenging. Molecular imaging holds promise here, when applied as a tool for image-guided surgery of DCIS. METHODS: Tissue microarrays containing 24 pure DCIS and 63 DCIS with adjacent invasive breast cancer cases were stained by immunohistochemistry for a panel of membrane-bound targets. RESULTS: GLUT1 expression was present in 60...
July 2013: Cellular Oncology (Dordrecht)
Johanna Chiche, Jean-Ehrland Ricci, Jacques Pouysségur
The transcription factor hypoxia-inducible factor-1 (HIF-1) facilitates the induction of enzymes necessary for regulation of biological processes required for cell survival and the acquisition of an aggressive and invasive phenotype, such as regulation of the intracellular pH (pHi), anaerobic glycolysis, angiogenesis, migration/invasion... In this presentation, we will highlight some of the HIF-1-induced gene products - carbonic anhydrases IX and XII (CAs) and monocarboxylate transporters (MCTs) - which regulate the pHi by controlling export of metabolically-generated acids (carbonic and lactic acids)...
May 2013: Annales D'endocrinologie
Yun-Long Liu, Li-Ling Jing, Qi-Sen Guo
OBJECTIVE: To assess the practical utility of pleural fluid carbonic anhydrase XII (CAXII) quantification for differential diagnosis of effusions. MATERIALS AND METHODS: Fluid was collected prospectively from fifty patients presenting with lymphocytic pleural effusions for investigation and CAXII was quantified by ELISA. RESULTS: Pleural fluid CAXII concentrations were significantly higher in lung cancer patients (n=30) than in tuberculous controls (n=20)...
2013: Asian Pacific Journal of Cancer Prevention: APJCP
Nadia Lounnas, Célia Rosilio, Marielle Nebout, Didier Mary, Emmanuel Griessinger, Zouhour Neffati, Johanna Chiche, Hergen Spits, Thijs J Hagenbeek, Vahid Asnafi, Sally-Ann Poulsen, Claudiu T Supuran, Jean-François Peyron, Véronique Imbert
The membrane-bound carbonic anhydrase isoforms CAIX and CAXII, underpin a pH-regulating system that enables hypoxic tumor cell survival. Here, we observed for the first time an upregulation of CAXII in T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LL) cells. First we showed that CAXII is overexpressed in thymocytes from tPTEN-/- mice suffering of T lymphoma and that its pharmacological inhibition decreased cell proliferation and induced apoptosis. The same results were observed with the SupT1 human T cell lymphoma line...
June 1, 2013: Cancer Letters
Jérome Doyen, Scott K Parks, Serge Marcié, Jacques Pouysségur, Johanna Chiche
The relationship between acidosis within the tumor microenvironment and radioresistance of hypoxic tumor cells remains unclear. Previously we reported that hypoxia-induced carbonic anhydrases (CA) IX and CAXII constitute a robust intracellular pH (pH(i))-regulating system that confers a survival advantage on hypoxic human colon carcinoma LS174Tr cells in acidic microenvironments. Here we investigate the role of acidosis, CAIX and CAXII knock-down in combination with ionizing radiation. Fibroblasts cells (-/+ CAIX) and LS174Tr cells (inducible knock-down for ca9/ca12) were analyzed for cell cycle phase distribution and survival after irradiation in extracellular pH(o) manipulations and hypoxia (1% O(2)) exposure...
2012: Frontiers in Oncology
Jeroen F Vermeulen, Robert Kornegoor, Elsken van der Wall, Petra van der Groep, Paul J van Diest
INTRODUCTION: Male breast cancer accounts for 0.5-1% of all breast cancers and is generally diagnosed at higher stage than female breast cancers and therefore might benefit from earlier detection and targeted therapy. Except for HER2 and EGFR, little is known about expression of growth factor receptors in male breast cancer. We therefore investigated expression profiles of growth factor receptors and membrane-bound tumor markers in male breast cancer and gynecomastia, in comparison with female breast cancer...
2013: PloS One
Reuven Reich, Amnon Hoffman, Ainelly Veerendhar, Alfonso Maresca, Alessio Innocenti, Claudiu T Supuran, Eli Breuer
Carbamoylphosphonates (CPOs) have been identified as inhibitors of matrix metalloproteinases (MMPs) and as orally active, bioavailable, and safe antimetastatic agents. In this article, we focus on the direct antitumor activity of the CPOs. We discovered that CPOs also inhibit carbonic anhydrases (CAs), especially the IX and XII isoforms identified as cancer promoting factors. Thus, CPOs can be regarded as novel nontoxic drug candidates for tumor microenvironment targeted chemotherapy acting by two synergistic mechanisms, namely, inhibiting CAs and MMPs simultaneously...
September 13, 2012: Journal of Medicinal Chemistry
Alan McIntyre, Shalini Patiar, Simon Wigfield, Ji-Liang Li, Ioanna Ledaki, Helen Turley, Russell Leek, Cameron Snell, Kevin Gatter, William S Sly, Richard D Vaughan-Jones, Pawel Swietach, Adrian L Harris
PURPOSE: Bevacizumab, an anti-VEGFA antibody, inhibits the developing vasculature of tumors, but resistance is common. Antiangiogenic therapy induces hypoxia and we observed increased expression of hypoxia-regulated genes, including carbonic anhydrase IX (CAIX), in response to bevacizumab treatment in xenografts. CAIX expression correlates with poor prognosis in most tumor types and with worse outcome in bevacizumab-treated patients with metastatic colorectal cancer, malignant astrocytoma, and recurrent malignant glioma...
June 1, 2012: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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