Trafficking of carbonic anhydrase 12 and bicarbonate transporters by histamine stimulation mediates intracellular acidic scenario in lung cancer cells

Abstract

Carbonic anhydrase 12 is considered an oncogenic and acidic microenvironmental factor in cancer cells. To verify the role of histamine signalling as an anti-cancer signal, we determined the roles of CA12 and its associated bicarbonate transporters. In this study, histamine stimulation mediated mislocalization of CA12 in lung cancer cells. Histamine receptor activation-mediated CA12 endocytosis and pH were restored by CaMKII inhibition. CA12-associated AE2 expression was enhanced, whereas NBCn1 expression and its activity were reduced by histamine stimulation. Histamine receptor activation-mediated acidification was induced by internalised CA12 and NBCn1 and, at the same time by increased bicarbonate efflux through enhanced AE2 expression. Inhibition of protein trafficking by bafilomycin restored CA12 and AE2 localisation and diminished cellular acidosis. Thus, we verified that histamine stimulation induced an acidic scenario, which revealed trafficking of CA12 and its associated bicarbonate transporters in lung cancer cells and its dysregulated pH modulation may be involved in the histamine signalling-mediated anti-cancer process.

Keywords:

• Carbonic anhydrase 12
• NBCn1
• AE2
• Acidic scenario
• Histamine

Acknowledgement

All figures were developed by the authors. All of the image data acquisition was performed at the Cell to In Vivo Imaging Core Facility Research Center (CII, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, South Korea).

Author contribution

HJK and JHH conceptualised and designed the study and acquired, analysed, and interpreted data; HJK and JHH drafted the manuscript and acquired data. JHH revised the manuscript critically for important intellectual content; JHH contributed to the funding acquisition and final approval of the published version and are responsible for all aspects of the work as regards the accuracy and integrity of the study.

Disclosure statement

The authors have no conflicts of interest to declare.

Additional information

Funding

This research was funded by the National Research Foundation of Korea (NRF) grant funded by the Korean government [MSIT; 2022R1A2C1003890: JHH].