Carbonic anhydrase XII is a new therapeutic target to overcome chemoresistance in cancer cells

// Joanna Kopecka 1, * , Ivana Campia 1, * , Andrea Jacobs 2 , Andreas P. Frei 2, 3 , Dario Ghigo 1 , Bernd Wollscheid 2, 3 , Chiara Riganti 1 1 Department of Oncology, University of Torino, 10126 Torino, Italy 2 Department of Biology, Institute of Molecular Systems Biology, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland 3 Biomedical Proteomics Platform (BMPP), Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland * These authors have contributed equally to this work Correspondence to: Chiara Riganti, e-mail: chiara.riganti@unito.it Keywords: chemoresistance, surfaceome, P-glycoprotein, carbonic anhydrase type XII Received: September 09, 2014 Accepted: December 09, 2014 Published: February 18, 2015 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.