Carbonic Anhydrase XII Expression Is Modulated during Epithelial Mesenchymal Transition and Regulated through Protein Kinase C Signaling

Int J Mol Sci. 2020 Jan 22;21(3):715. doi: 10.3390/ijms21030715.


Members of the carbonic anhydrase family are functionally involved in the regulation of intracellular and extracellular pH in physiological and pathological conditions. Their expression is finely regulated to maintain a strict control on cellular homeostasis, and it is dependent on the activation of extracellular and intracellular signaling pathways. Combining RNA sequencing (RNA-seq), NanoString, and bioinformatics data, we demonstrated that the expression of carbonic anhydrase 12 (CAXII) is significantly different in luminal and triple negative breast cancer (BC) models and patients, and is associated with the activation of an epithelial mesenchymal transition (EMT) program. In BC models, the phorbol ester 12-myristate 13-acetate (PMA)-mediated activation of protein kinase C (PKC) induced a down-regulation of CAXII with a concomitant modulation of other members of the transport metabolon, including CAIX and the sodium bicarbonate cotransporter 3 (NBCn1). This is associated with a remodeling of tumor glycolytic metabolism induced after PKC activation. Overall, this analysis highlights the dynamic nature of transport metabolom and identifies signaling pathways finely regulating this plasticity.

Keywords: PKC; breast cancer; carbonic anhydrase; epithelial mesenchymal transition; metabolism; proteomics; transport metabolon.

MeSH terms

  • Adult
  • Aged
  • Antigens, Neoplasm / genetics
  • Carbonic Anhydrases / genetics*
  • Cell Line, Tumor
  • Down-Regulation / genetics
  • Epithelial-Mesenchymal Transition / genetics*
  • Female
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • MCF-7 Cells
  • Middle Aged
  • Protein Kinase C / genetics*
  • Signal Transduction / genetics
  • Sodium-Bicarbonate Symporters / genetics
  • Triple Negative Breast Neoplasms / genetics


  • Antigens, Neoplasm
  • Sodium-Bicarbonate Symporters
  • Protein Kinase C
  • CA13 protein, human
  • Carbonic Anhydrases