title: Carbonic anhydrase XII is a new therapeutic target to overcome chemoresistance in cancer cells.
abstract: 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. In cellular models showing an acquired MDR phenotype due to the selective pressure of chemotherapy, the progressive increase of the transcription factor hypoxia-inducible factor-1 alpha was paralleled by the simultaneous up-regulation of Pgp and CAXII. CAXII and Pgp physically interacted at the cell surface. CAXII silencing or pharmacological inhibition with acetazolamide decreased the ATPase activity of Pgp by altering the optimal pH at which Pgp operated and promoted chemosensitization to Pgp substrates in MDR cells.We propose CAXII as a new secondary marker of the MDR phenotype that influences Pgp activity directly and can be used as a pharmacological target for MDR research and potential treatment.
authors: Department of Oncology, University of Torino, 10126 Torino, Italy.
authors: Joanna
authors: J
authors: Kopecka
authors: Department of Oncology, University of Torino, 10126 Torino, Italy.
authors: Ivana
authors: I
authors: Campia
authors: Department of Biology, Institute of Molecular Systems Biology, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland.
authors: Andrea
authors: A
authors: Jacobs
authors: Department of Biology, Institute of Molecular Systems Biology, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland.|Biomedical Proteomics Platform (BMPP), Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland.
authors: Andreas P
authors: AP
authors: Frei
authors: Department of Oncology, University of Torino, 10126 Torino, Italy.
authors: Dario
authors: D
authors: Ghigo
authors: Department of Biology, Institute of Molecular Systems Biology, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland.|Biomedical Proteomics Platform (BMPP), Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland.
authors: Bernd
authors: B
authors: Wollscheid
authors: Department of Oncology, University of Torino, 10126 Torino, Italy.
authors: Chiara
authors: C
authors: Riganti
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D049109:Cell Proliferation / Q000187:drug effects; D061505:Cell Surface Display Techniques; D016922:Cellular Senescence / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D019073:HT29 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D058990:Molecular Targeted Therapy; D010641:Phenotype; D040901:Proteomics / Q000379:methods; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D002257:Carbonic Anhydrase Inhibitors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D004317:Doxorubicin; D002256:Carbonic Anhydrases; C477378:carbonic anhydrase XII
keywords: P-glycoprotein; carbonic anhydrase type XII; chemoresistance; surfaceome