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.

An inhibitory antibody targeting carbonic anhydrase XII abrogates chemoresistance and significantly reduces lung metastases in an orthotopic breast cancer model in vivo

“…It has been demonstrated recently that CAXII and P‐GP are co‐expressed in many chemoresistant human cancers, that CAXII activity is relevant for the chemoresistant phenotype of these cells, and that a silencing of CAXII with siRNAs restores chemosensitivity . Because this type of intervention is not possible in vivo , we investigated whether the CAXII‐inhibitory antibody 6A10 also interferes with P‐GP‐mediated chemoresistance.…”

“…The molecular mode of action of how 6A10 interferes with P‐GP activity is not fully understood, but given that both proteins interact physically, it is tempting to speculate that CAXII inhibition locally perturbs intracellular pH regulation and thus P‐GP activity. Indeed, the optimal pH at which P‐GP works is around 7.6; transiently CAXII inhibition and/or pharmacological inhibition with the broad‐spectrum CA inhibitor acetazolamide lowers the pH at 7.4, decreasing P‐GP activity by about 25% …”

“…Of note, it has been demonstrated recently that CAXII physically interacts with, and regulates the activity of, P‐GP and in chemoresistant cancer cells . In addition, a genetic CAXII knock‐down in P‐GP‐positive cancer cell lines resulted in enhanced chemosensitivity .…”

“…14,15 Of note, it has been demonstrated recently that CAXII physically interacts with, and regulates the activity of, P-GP and in chemoresistant cancer cells. 16,17 In addition, a genetic CAXII knock-down in P-GP-positive cancer cell lines resulted in enhanced chemosensitivity. 16 We show here that the blocking CAXII-specific monoclonal antibody 6A10 interferes with P-GP activity in chemoresistant cancer cell lines, thus increasing the sensitivity against clinically relevant anthracyclines.…”

Cancer cell behaviors mediated by dysregulated pH dynamics at a glance

“…This leads to a growing consensus in the field of cancer research that approaches targeting increased pH i are clinically promising (Neri and Supuran, 2011;Kopecka et al, 2015;Pedersen and Stock, 2013), particularly in cases where other targeted therapies have failed (Gillies et al, 2012;Alfarouk et al, 2015). Supporting this idea, lowering pH i through genetic knockdown or inhibition of ion transporters reduces cell proliferation and migration Amith et al, 2016a;Le Floch et al, 2011), cell invasion (Yang et al, 2010), and suppresses tumorigenesis in xenograft models (Amith et al, 2015;Lagarde et al, 1988;Sonveaux et al, 2008;Colen et al, 2011;Chiche et al, 2012).…”