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Bettina von Neubeck, Gabor Gondi, Chiara Riganti, Chenchen Pan, Arnaldo Parra Damas, Hagen Scherb, Ali Ertürk, Reinhard Zeidler
Carbonic Anhydrase XII (CAXII) is a membrane-tethered ectoenzyme involved in intracellular pH regulation and overexpressed across various types of human cancer. Because CAXII inhibition shows antitumour activity in vitro, it is thought that the enzyme is mandatory for maximum tumour growth, above all under hypoxic conditions. Recently, it has been shown that CAXII is co-expressed along with the P-glycoprotein (P-GP) on many tumour cells and that both proteins physically interact. Of interest, blocking CAXII activity also decreases P-GP activity in cancer cells both in vitro and in vivo...
May 22, 2018: International Journal of Cancer. Journal International du Cancer
Serge D Zemerov, Benjamin W Roose, Mara L Greenberg, Yanfei Wang, Ivan J Dmochowski
Cryptophane-based biosensors are promising agents for the ultrasensitive detection of biomedically relevant targets via 129Xe NMR. Dynamic light scattering revealed that cryptophanes form water-soluble aggregates of tens-to-hundreds of nanometers in size. Acridine orange fluorescence quenching assays allowed quantitation of aggregation state, with critical concentration rang-ing from 200 to 600 nM, depending on the cryptophane species in solution. Addition of excess carbonic anhydrase (CA) pro-tein target to a benzenesulfonamide-functionalized cryptophane biosensor (C8B) led to C8B disaggregation and produced the expected 1:1 C8B-CA complex...
May 21, 2018: Analytical Chemistry
Paul C McDonald, Mridula Swayampakula, Shoukat Dedhar
Hypoxia is a prominent feature of the tumor microenvironment (TME) and cancer cells must dynamically adapt their metabolism to survive in these conditions. A major consequence of metabolic rewiring by cancer cells in hypoxia is the accumulation of acidic metabolites, leading to the perturbation of intracellular pH (pHi) homeostasis and increased acidosis in the TME. To mitigate the potentially detrimental consequences of an increasingly hypoxic and acidic TME, cancer cells employ a network of enzymes and transporters to regulate pH, particularly the extracellular facing carbonic anhydrase IX (CAIX) and CAXII...
March 8, 2018: Metabolites
Damien Ambrosetti, Maeva Dufies, Bérengère Dadone, Matthieu Durand, Delphine Borchiellini, Jean Amiel, Jacques Pouyssegur, Nathalie Rioux-Leclercq, Gilles Pages, Fanny Burel-Vandenbos, Nathalie M Mazure
BACKGROUND: Clear-cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer. Although ccRCC is characterized by common recurrent genetic abnormalities, including inactivation of the von Hippel-Lindau (vhl) tumor suppressor gene resulting in stabilization of hypoxia-inducible factors (HIFs), the tumor aggressiveness and outcome of ccRCC is variable. New biomarkers are thus required to improve ccRCC diagnosis, prognosis and therapeutic options. This work aims to investigate the expression of HIF and proteins involved in metabolism and pH regulation...
2018: PloS One
Zhenyu Wang, Jiali Leng, Yuguang Zhao, Dehai Yu, Feng Xu, Qingxu Song, Zhigang Qu, Xinming Zhuang, Yi Liu
BACKGROUND/AIMS: Mechanical load can regulate disc nucleus pulposus (NP) biology in terms of cell viability, matrix homeostasis and cell phenotype. N-cadherin (N-CDH) is a molecular marker of NP cells. This study investigated the role of N-CDH in maintaining NP cell phenotype, NP matrix synthesis and NP cell viability under high-magnitude compression. METHODS: Rat NP cells seeded on scaffolds were perfusion-cultured using a self-developed perfusion bioreactor for 5 days...
October 27, 2017: Cellular Physiology and Biochemistry
Véronique Imbert, Marielle Nebout, Didier Mary, Hitoshi Endou, Michael F Wempe, Claudiu T Supuran, Jean-Yves Winum, Jean-François Peyron
Cancer cells reprogram their metabolism to optimize their growth and proliferation in the host microenvironment. For this purpose, they enhance the uptake of extracellular nutrients and deal with the metabolic waste products through the overexpression of numerous membrane proteins including amino-acid transporters (LAT1) and acid-base regulating enzymes, such as carbonic anhydrases (CAs). Here we describe the anti-tumoral effects of a new class of CAXII inhibitors, the glycosyl coumarins on T-ALL/LL cells. These effects appeared to be mediated through inhibition of mTOR/Akt pathway and c-myc downregulation...
June 22, 2017: Leukemia & Lymphoma
Abdul Waheed, William S Sly
Human CAXII was initially identified as a cancer marker in different cancers and tumors. Expression of CAXII is regulated by hypoxia and estrogen receptors. CAXII expression has been also detected in several tissues, whereas in cancer and tumor tissues its expression is several fold higher. In brain tumors, an alternatively spliced form of CAXII is expressed. Higher expression of CAXII in breast cancer is indicative of lower grade disease. CAXII plays a key role in several physiological functions. Mutation in the CAXII gene causes cystic fibrosis-like syndrome and salt wasting disease...
August 5, 2017: Gene
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...
December 27, 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...
December 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)
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