Abstract
Human carbonic anhydrases IX (hCA IX) and XII (hCA XII) are two proteins associated with tumor formation and development. These enzymes have been largely investigated both from a biochemical and a functional point of view. However, limited data are currently available on the characterization of their post-translational modifications (PTMs) and the functional implication of these structural changes in the tumor environment. In this review, we summarize existing literature data on PTMs of hCA IX and hCA XII, such as disulphide bond formation, phosphorylation, O-/N-linked glycosylation, acetylation and ubiquitination, highlighting, when possible, their specific role in cancer pathological processes.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Abbreviations
- ADC:
-
Antibody–drug conjugate
- AE:
-
Anion exchanger
- CA:
-
Carbonic anhydrase
- ER alpha:
-
Estrogen receptor alpha
- GAG:
-
Glycosaminoglycan
- hCA:
-
Human carbonic anhydrase
- HIF-1:
-
Hypoxia-inducible factor 1
- IC:
-
Intracellular tail
- IDP:
-
Intrinsically disordered protein
- MCT:
-
Monocarboxylate transporter
- MMP14:
-
Metalloproteinase 14
- NBC:
-
Na+/bicarbonate co-transporter
- NHE:
-
Na+/H+exchanger
- PG:
-
Proteoglycan-like domain
- pHi:
-
Intracellular pH
- pHe:
-
Extracellular pH
- PKA:
-
Protein kinase A
- PTM:
-
Post-translational modification
- RCC:
-
Renal cell carcinoma
- SP:
-
Signal peptide
- TM:
-
Transmembrane region
- V-ATPase:
-
V-type H+ ATPase
References
Aggarwal M, Boone CD, Kondeti B, McKenna R (2013) Structural annotation of human carbonic anhydrases. J Enzyme Inhib Med Chem 28(2):267–277. https://doi.org/10.3109/14756366.2012.737323
Aggarwal M, Kondeti B, Tu C, Maupin CM, Silverman DN, McKenna R (2014) Structural insight into activity enhancement and inhibition of H64A carbonic anhydrase II by imidazoles. IUCrJ 1(Pt 2):129–135. https://doi.org/10.1107/S2052252514004096
Ahuja LG, Aoto PC, Kornev AP, Veglia G, Taylor SS (2019) Dynamic allostery-based molecular workings of kinase: peptide complexes. Proc Natl Acad Sci USA 116(30):15052–15061. https://doi.org/10.1073/pnas.1900163116
Alterio V, Hilvo M, Di Fiore A, Supuran CT, Pan P, Parkkila S, Scaloni A, Pastorek J, Pastorekova S, Pedone C, Scozzafava A, Monti SM, De Simone G (2009) Crystal structure of the catalytic domain of the tumor-associated human carbonic anhydrase IX. Proc Natl Acad Sci USA 106(38):16233–16238. https://doi.org/10.1073/pnas.0908301106
Alterio V, Di Fiore A, D’Ambrosio K, Supuran CT, De Simone G (2012) Multiple binding modes of inhibitors to carbonic anhydrases: how to design specific drugs targeting 15 different isoforms? Chem Rev 112(8):4421–4468. https://doi.org/10.1021/cr200176r
Alterio V, Pan P, Parkkila S, Buonanno M, Supuran CT, Monti SM, De Simone G (2014) The structural comparison between membrane-associated human carbonic anhydrases provides insights into drug design of selective inhibitors. Biopolymers 101(7):769–778. https://doi.org/10.1002/bip.22456
Alterio V, Kellner M, Esposito D, Liesche-Starnecker F, Bua S, Supuran CT, Monti SM, Zeidler R, De Simone G (2019) Biochemical and structural insights into carbonic anhydrase XII/Fab6A10 complex. J Mol Biol 431(24):4910–4921. https://doi.org/10.1016/j.jmb.2019.10.022
Ames S, Pastorekova S, Becker HM (2018) The proteoglycan-like domain of carbonic anhydrase IX mediates non-catalytic facilitation of lactate transport in cancer cells. Oncotarget 9(46):27940–27957. https://doi.org/10.18632/oncotarget.25371
An Y, Zhou L, Huang Z, Nice EC, Zhang H, Huang C (2019) Molecular insights into cancer drug resistance from a proteomics perspective. Expert Rev Proteomics 16(5):413–429. https://doi.org/10.1080/14789450.2019.1601561
Angeli A, Carta F, Nocentini A, Winum JY, Zalubovskis R, Akdemir A, Onnis V, Eldehna WM, Capasso C, De Simone G, Monti SM, Carradori S, Donald WA, Dedhar S, Supuran CT (2020) Carbonic anhydrase inhibitors targeting metabolism and tumor microenvironment. Metabolites. https://doi.org/10.3390/metabo10100412
Barnett DH, Sheng S, Charn TH, Waheed A, Sly WS, Lin CY, Liu ET, Katzenellenbogen BS (2008) Estrogen receptor regulation of carbonic anhydrase XII through a distal enhancer in breast cancer. Cancer Res 68(9):3505–3515. https://doi.org/10.1158/0008-5472.CAN-07-6151
Battke C, Kremmer E, Mysliwietz J, Gondi G, Dumitru C, Brandau S, Lang S, Vullo D, Supuran C, Zeidler R (2011) Generation and characterization of the first inhibitory antibody targeting tumour-associated carbonic anhydrase XII. Cancer Immunol Immunother 60(5):649–658. https://doi.org/10.1007/s00262-011-0980-z
Boone CD, Pinard M, McKenna R, Silverman D (2014) Catalytic mechanism of alpha-class carbonic anhydrases: CO2 hydration and proton transfer. Subcell Biochem 75:31–52. https://doi.org/10.1007/978-94-007-7359-2_3
Buanne P, Renzone G, Monteleone F, Vitale M, Monti SM, Sandomenico A, Garbi C, Montanaro D, Accardo M, Troncone G, Zatovicova M, Csaderova L, Supuran CT, Pastorekova S, Scaloni A, De Simone G, Zambrano N (2013) Characterization of carbonic anhydrase IX interactome reveals proteins assisting its nuclear localization in hypoxic cells. J Proteome Res 12(1):282–292. https://doi.org/10.1021/pr300565w
Buonanno M, Langella E, Zambrano N, Succoio M, Sasso E, Alterio V, Di Fiore A, Sandomenico A, Supuran CT, Scaloni A, Monti SM, De Simone G (2017) Disclosing the interaction of carbonic anhydrase IX with cullin-associated NEDD8-dissociated protein 1 by molecular modeling and integrated binding measurements. ACS Chem Biol 12(6):1460–1465. https://doi.org/10.1021/acschembio.7b00055
Buren S, Ortega-Villasante C, Blanco-Rivero A, Martinez-Bernardini A, Shutova T, Shevela D, Messinger J, Bako L, Villarejo A, Samuelsson G (2011) Importance of post-translational modifications for functionality of a chloroplast-localized carbonic anhydrase (CAH1) in Arabidopsis thaliana. PLoS ONE 6(6):e21021. https://doi.org/10.1371/journal.pone.0021021
Chen L, Liu S, Tao Y (2020) Regulating tumor suppressor genes: post-translational modifications. Signal Transduct Target Ther 5(1):90. https://doi.org/10.1038/s41392-020-0196-9
Chia SK, Wykoff CC, Watson PH, Han C, Leek RD, Pastorek J, Gatter KC, Ratcliffe P, Harris AL (2001) Prognostic significance of a novel hypoxia-regulated marker, carbonic anhydrase IX, in invasive breast carcinoma. J Clin Oncol 19(16):3660–3668. https://doi.org/10.1200/JCO.2001.19.16.3660
Chiche J, Ilc K, Laferriere J, Trottier E, Dayan F, Mazure NM, Brahimi-Horn MC, Pouyssegur J (2009) Hypoxia-inducible carbonic anhydrase IX and XII promote tumor cell growth by counteracting acidosis through the regulation of the intracellular pH. Cancer Res 69(1):358–368. https://doi.org/10.1158/0008-5472.CAN-08-2470
Christianson HC, Menard JA, Chandran VI, Bourseau-Guilmain E, Shevela D, Lidfeldt J, Mansson AS, Pastorekova S, Messinger J, Belting M (2017) Tumor antigen glycosaminoglycan modification regulates antibody-drug conjugate delivery and cytotoxicity. Oncotarget 8(40):66960–66974. https://doi.org/10.18632/oncotarget.16921
Csaderova L, Debreova M, Radvak P, Stano M, Vrestiakova M, Kopacek J, Pastorekova S, Svastova E (2013) The effect of carbonic anhydrase IX on focal contacts during cell spreading and migration. Front Physiol 4:271. https://doi.org/10.3389/fphys.2013.00271
Debreova M, Csaderova L, Burikova M, Lukacikova L, Kajanova I, Sedlakova O, Kery M, Kopacek J, Zatovicova M, Bizik J, Pastorekova S, Svastova E (2019) CAIX regulates invadopodia formation through both a pH-dependent mechanism and interplay with actin regulatory proteins. Int J Mol Sci. https://doi.org/10.3390/ijms20112745
Di Fiore A, Supuran CT, Scaloni A, De Simone G (2020) Human carbonic anhydrases and post-translational modifications: a hidden world possibly affecting protein properties and functions. J Enzyme Inhib Med Chem 35(1):1450–1461. https://doi.org/10.1080/14756366.2020.1781846
Ditte P, Dequiedt F, Svastova E, Hulikova A, Ohradanova-Repic A, Zatovicova M, Csaderova L, Kopacek J, Supuran CT, Pastorekova S, Pastorek J (2011) Phosphorylation of carbonic anhydrase IX controls its ability to mediate extracellular acidification in hypoxic tumors. Cancer Res 71(24):7558–7567. https://doi.org/10.1158/0008-5472.CAN-11-2520
Divgi CR, Uzzo RG, Gatsonis C, Bartz R, Treutner S, Yu JQ, Chen D, Carrasquillo JA, Larson S, Bevan P, Russo P (2013) Positron emission tomography/computed tomography identification of clear cell renal cell carcinoma: results from the REDECT trial. J Clin Oncol 31(2):187–194. https://doi.org/10.1200/JCO.2011.41.2445
Domsic JF, Avvaru BS, Kim CU, Gruner SM, Agbandje-McKenna M, Silverman DN, McKenna R (2008) Entrapment of carbon dioxide in the active site of carbonic anhydrase II. J Biol Chem 283(45):30766–30771. https://doi.org/10.1074/jbc.M805353200
Dorai T, Sawczuk IS, Pastorek J, Wiernik PH, Dutcher JP (2005) The role of carbonic anhydrase IX overexpression in kidney cancer. Eur J Cancer 41(18):2935–2947. https://doi.org/10.1016/j.ejca.2005.09.011
Doyen J, Parks SK, Marcie S, Pouyssegur J, Chiche J (2012) Knock-down of hypoxia-induced carbonic anhydrases IX and XII radiosensitizes tumor cells by increasing intracellular acidosis. Front Oncol 2:199. https://doi.org/10.3389/fonc.2012.00199
Doyle HA, Mamula MJ (2001) Post-translational protein modifications in antigen recognition and autoimmunity. Trends Immunol 22(8):443–449. https://doi.org/10.1016/s1471-4906(01)01976-7
Feinstein Y, Yerushalmi B, Loewenthal N, Alkrinawi S, Birk OS, Parvari R, Hershkovitz E (2014) Natural history and clinical manifestations of hyponatremia and hyperchlorhidrosis due to carbonic anhydrase XII deficiency. Horm Res Paediatr 81(5):336–342. https://doi.org/10.1159/000358327
Feldshtein M, Elkrinawi S, Yerushalmi B, Marcus B, Vullo D, Romi H, Ofir R, Landau D, Sivan S, Supuran CT, Birk OS (2010) Hyperchlorhidrosis caused by homozygous mutation in CA12, encoding carbonic anhydrase XII. Am J Hum Genet 87(5):713–720. https://doi.org/10.1016/j.ajhg.2010.10.008
Filtz TM, Vogel WK, Leid M (2014) Regulation of transcription factor activity by interconnected post-translational modifications. Trends Pharmacol Sci 35(2):76–85. https://doi.org/10.1016/j.tips.2013.11.005
Fisher SZ, Maupin CM, Budayova-Spano M, Govindasamy L, Tu C, Agbandje-McKenna M, Silverman DN, Voth GA, McKenna R (2007) Atomic crystal and molecular dynamics simulation structures of human carbonic anhydrase II: insights into the proton transfer mechanism. Biochemistry 46(11):2930–2937. https://doi.org/10.1021/bi062066y
Funderburgh JL (2000) Keratan sulfate: structure, biosynthesis, and function. Glycobiology 10(10):951–958. https://doi.org/10.1093/glycob/10.10.951
Giatromanolaki A, Koukourakis MI, Sivridis E, Pastorek J, Wykoff CC, Gatter KC, Harris AL (2001) Expression of hypoxia-inducible carbonic anhydrase-9 relates to angiogenic pathways and independently to poor outcome in non-small cell lung cancer. Cancer Res 61(21):7992–7998
Gieling RG, Babur M, Mamnani L, Burrows N, Telfer BA, Carta F, Winum JY, Scozzafava A, Supuran CT, Williams KJ (2012) Antimetastatic effect of sulfamate carbonic anhydrase IX inhibitors in breast carcinoma xenografts. J Med Chem 55(11):5591–5600. https://doi.org/10.1021/jm300529u
Gil J, Ramirez-Torres A, Encarnacion-Guevara S (2017) Lysine acetylation and cancer: a proteomics perspective. J Proteomics 150:297–309. https://doi.org/10.1016/j.jprot.2016.10.003
Gondi G, Mysliwietz J, Hulikova A, Jen JP, Swietach P, Kremmer E, Zeidler R (2013) Antitumor efficacy of a monoclonal antibody that inhibits the activity of cancer-associated carbonic anhydrase XII. Cancer Res 73(21):6494–6503. https://doi.org/10.1158/0008-5472.CAN-13-1110
Gruber W, Scheidt T, Aberger F, Huber CG (2017) Understanding cell signaling in cancer stem cells for targeted therapy—can phosphoproteomics help to reveal the secrets? Cell Commun Signal 15(1):12. https://doi.org/10.1186/s12964-017-0166-1
Gudiksen KL, Gitlin I, Yang J, Urbach AR, Moustakas DT, Whitesides GM (2005) Eliminating positively charged lysine epsilon-NH3+ groups on the surface of carbonic anhydrase has no significant influence on its folding from sodium dodecyl sulfate. J Am Chem Soc 127(13):4707–4714. https://doi.org/10.1021/ja043804d
Gupta R, Brunak S (2002) Prediction of glycosylation across the human proteome and the correlation to protein function. Pacific Symposium on Biocomputing, 310–322
Haapasalo J, Hilvo M, Nordfors K, Haapasalo H, Parkkila S, Hyrskyluoto A, Rantala I, Waheed A, Sly WS, Pastorekova S, Pastorek J, Parkkila AK (2008) Identification of an alternatively spliced isoform of carbonic anhydrase XII in diffusely infiltrating astrocytic gliomas. Neuro Oncol 10(2):131–138. https://doi.org/10.1215/15228517-2007-065
Hernandez-Valladares M, Wangen R, Berven FS, Guldbrandsen A (2019) Protein post-translational modification crosstalk in acute myeloid leukemia calls for action. Curr Med Chem 26(28):5317–5337. https://doi.org/10.2174/0929867326666190503164004
Hilvo M, Baranauskiene L, Salzano AM, Scaloni A, Matulis D, Innocenti A, Scozzafava A, Monti SM, Di Fiore A, De Simone G, Lindfors M, Janis J, Valjakka J, Pastorekova S, Pastorek J, Kulomaa MS, Nordlund HR, Supuran CT, Parkkila S (2008) Biochemical characterization of CA IX, one of the most active carbonic anhydrase isozymes. J Biol Chem 283(41):27799–27809. https://doi.org/10.1074/jbc.M800938200
Hong JH, Muhammad E, Zheng C, Hershkovitz E, Alkrinawi S, Loewenthal N, Parvari R, Muallem S (2015) Essential role of carbonic anhydrase XII in secretory gland fluid and HCO3 (-) secretion revealed by disease causing human mutation. J Physiol 593(24):5299–5312. https://doi.org/10.1113/JP271378
Hsieh MJ, Chen KS, Chiou HL, Hsieh YS (2010) Carbonic anhydrase XII promotes invasion and migration ability of MDA-MB-231 breast cancer cells through the p38 MAPK signaling pathway. Eur J Cell Biol 89(8):598–606. https://doi.org/10.1016/j.ejcb.2010.03.004
Hulikova A, Zatovicova M, Svastova E, Ditte P, Brasseur R, Kettmann R, Supuran CT, Kopacek J, Pastorek J, Pastorekova S (2009) Intact intracellular tail is critical for proper functioning of the tumor-associated, hypoxia-regulated carbonic anhydrase IX. FEBS Lett 583(22):3563–3568. https://doi.org/10.1016/j.febslet.2009.10.060
Hynninen P, Vaskivuo L, Saarnio J, Haapasalo H, Kivela J, Pastorekova S, Pastorek J, Waheed A, Sly WS, Puistola U, Parkkila S (2006) Expression of transmembrane carbonic anhydrases IX and XII in ovarian tumours. Histopathology 49(6):594–602. https://doi.org/10.1111/j.1365-2559.2006.02523.x
Ilardi G, Zambrano N, Merolla F, Siano M, Varricchio S, Vecchione M, De Rosa G, Mascolo M, Staibano S (2014) Histopathological determinants of tumor resistance: a special look to the immunohistochemical expression of carbonic anhydrase IX in human cancers. Curr Med Chem 21(14):1569–1582
Innocenti A, Pastorekova S, Pastorek J, Scozzafava A, De Simone G, Supuran CT (2009) The proteoglycan region of the tumor-associated carbonic anhydrase isoform IX acts as anintrinsic buffer optimizing CO2 hydration at acidic pH values characteristic of solid tumors. Bioorg Med Chem Lett 19(20):5825–5828. https://doi.org/10.1016/j.bmcl.2009.08.088
Ivanov SV, Kuzmin I, Wei MH, Pack S, Geil L, Johnson BE, Stanbridge EJ, Lerman MI (1998) Down-regulation of transmembrane carbonic anhydrases in renal cell carcinoma cell lines by wild-type von Hippel-Lindau transgenes. Proc Natl Acad Sci USA 95(21):12596–12601. https://doi.org/10.1073/pnas.95.21.12596
Jamali S, Klier M, Ames S, Barros LF, McKenna R, Deitmer JW, Becker HM (2015) Hypoxia-induced carbonic anhydrase IX facilitates lactate flux in human breast cancer cells by non-catalytic function. Sci Rep 5:13605. https://doi.org/10.1038/srep13605
Jonathan RA, Wijffels KI, Peeters W, de Wilde PC, Marres HA, Merkx MA, Oosterwijk E, van der Kogel AJ, Kaanders JH (2006) The prognostic value of endogenous hypoxia-related markers for head and neck squamous cell carcinomas treated with ARCON. Radiother Oncol 79(3):288–297. https://doi.org/10.1016/j.radonc.2006.04.008
Kailemia MJ, Park D, Lebrilla CB (2017) Glycans and glycoproteins as specific biomarkers for cancer. Anal Bioanal Chem 409(2):395–410. https://doi.org/10.1007/s00216-016-9880-6
Kalavska K, Cierna Z, Chovanec M, Takacova M, Svetlovska D, Miskovska V, Obertova J, Palacka P, Rajec J, Sycova-Mila Z, Machalekova K, Kajo K, Spanik S, Mardiak J, Babal P, Pastorekova S, Mego M (2017) Prognostic value of intratumoral carbonic anhydrase IX expression in testicular germ cell tumors. Oncol Lett 13(4):2177–2185. https://doi.org/10.3892/ol.2017.5745
Kaluz S, Kaluzova M, Liao SY, Lerman M, Stanbridge EJ (2009) Transcriptional control of the tumor- and hypoxia-marker carbonic anhydrase 9: a one transcription factor (HIF-1) show? Biochim Biophys Acta 1795(2):162–172. https://doi.org/10.1016/j.bbcan.2009.01.001
Kang K, Choi JM, Fox JM, Snyder PW, Moustakas DT, Whitesides GM (2016) Acetylation of surface lysine groups of a protein alters the organization and composition of its crystal contacts. J Phys Chem B 120(27):6461–6468. https://doi.org/10.1021/acs.jpcb.6b01105
Karhumaa P, Parkkila S, Tureci O, Waheed A, Grubb JH, Shah G, Parkkila A, Kaunisto K, Tapanainen J, Sly WS, Rajaniemi H (2000) Identification of carbonic anhydrase XII as the membrane isozyme expressed in the normal human endometrial epithelium. Mol Hum Reprod 6(1):68–74. https://doi.org/10.1093/molehr/6.1.68
Karhumaa P, Kaunisto K, Parkkila S, Waheed A, Pastorekova S, Pastorek J, Sly WS, Rajaniemi H (2001) Expression of the transmembrane carbonic anhydrases, CA IX and CA XII, in the human male excurrent ducts. Mol Hum Reprod 7(7):611–616. https://doi.org/10.1093/molehr/7.7.611
Kazokaitė J, Niemans R, Dudutienė V, Becker HM, Leitāns J, Zubrienė A, Baranauskienė L, Gondi G, Zeidler R, Matulienė J, Tārs K, Yaromina A, Lambin P, Dubois LJ, Matulis D (2018) Novel fluorinated carbonic anhydrase IX inhibitors reduce hypoxia-induced acidification and clonogenic survival of cancer cells. Oncotarget 9(42):26800–26816. https://doi.org/10.18632/oncotarget.25508
Khoury GA, Baliban RC, Floudas CA (2011) Proteome-wide post-translational modification statistics: frequency analysis and curation of the swiss-prot database. Sci Rep. https://doi.org/10.1038/srep00090
Kivela A, Parkkila S, Saarnio J, Karttunen TJ, Kivela J, Parkkila AK, Waheed A, Sly WS, Grubb JH, Shah G, Tureci O, Rajaniemi H (2000a) Expression of a novel transmembrane carbonic anhydrase isozyme XII in normal human gut and colorectal tumors. Am J Pathol 156(2):577–584. https://doi.org/10.1016/S0002-9440(10)64762-1
Kivela AJ, Parkkila S, Saarnio J, Karttunen TJ, Kivela J, Parkkila AK, Pastorekova S, Pastorek J, Waheed A, Sly WS, Rajaniemi H (2000b) Expression of transmembrane carbonic anhydrase isoenzymes IX and XII in normal human pancreas and pancreatic tumours. Histochem Cell Biol 114(3):197–204
Kivela AJ, Parkkila S, Saarnio J, Karttunen TJ, Kivela J, Parkkila AK, Bartosova M, Mucha V, Novak M, Waheed A, Sly WS, Rajaniemi H, Pastorekova S, Pastorek J (2005) Expression of von Hippel-Lindau tumor suppressor and tumor-associated carbonic anhydrases IX and XII in normal and neoplastic colorectal mucosa. World J Gastroenterol 11(17):2616–2625
Kivela AJ, Knuuttila A, Rasanen J, Sihvo E, Salmenkivi K, Saarnio J, Pastorekova S, Pastorek J, Waheed A, Sly WS, Salo JA, Parkkila S (2013) Carbonic anhydrase IX in malignant pleural mesotheliomas: a potential target for anti-cancer therapy. Bioorg Med Chem 21(6):1483–1488. https://doi.org/10.1016/j.bmc.2012.09.018
Kowalewska M, Radziszewski J, Kulik J, Barathova M, Nasierowska-Guttmajer A, Bidzinski M, Pastorek J, Pastorekova S, Siedlecki JA (2005) Detection of carbonic anhydrase 9-expressing tumor cells in the lymph nodes of vulvar carcinoma patients by RT-PCR. Int J Cancer 116(6):957–962. https://doi.org/10.1002/ijc.21106
Langella E, Buonanno M, Vullo D, Dathan N, Leone M, Supuran CT, De Simone G, Monti SM (2018) Biochemical, biophysical and molecular dynamics studies on the proteoglycan-like domain of carbonic anhydrase IX. Cell Mol Life Sci 75(17):3283–3296. https://doi.org/10.1007/s00018-018-2798-8
Langella E, Buonanno M, De Simone G, Monti SM (2021) Intrinsically disordered features of carbonic anhydrase IX proteoglycan-like domain. Cell Mol Life Sci 78(5):2059–2067. https://doi.org/10.1007/s00018-020-03697-3
Lee M, Vecchio-Pagan B, Sharma N, Waheed A, Li X, Raraigh KS, Robbins S, Han ST, Franca AL, Pellicore MJ, Evans TA, Arcara KM, Nguyen H, Luan S, Belchis D, Hertecant J, Zabner J, Sly WS, Cutting GR (2016) Loss of carbonic anhydrase XII function in individuals with elevated sweat chloride concentration and pulmonary airway disease. Hum Mol Genet 25(10):1923–1933. https://doi.org/10.1093/hmg/ddw065
Leitans J, Kazaks A, Balode A, Ivanova J, Zalubovskis R, Supuran CT, Tars K (2015) Efficient expression and crystallization system of cancer-associated carbonic anhydrase isoform IX. J Med Chem 58(22):9004–9009. https://doi.org/10.1021/acs.jmedchem.5b01343
Li J, Zhan X (2021) Mass spectrometry-based proteomics analyses of post-translational modifications and proteoforms in human pituitary adenomas. Biochim Biophys Acta Proteins Proteom. https://doi.org/10.1016/j.bbapap.2020.140584
Li Y, Tu C, Wang H, Silverman DN, Frost SC (2011) Catalysis and pH control by membrane-associated carbonic anhydrase IX in MDA-MB-231 breast cancer cells. J Biol Chem 286(18):15789–15796. https://doi.org/10.1074/jbc.M110.188524
Liao SY, Brewer C, Zavada J, Pastorek J, Pastorekova S, Manetta A, Berman ML, DiSaia PJ, Stanbridge EJ (1994) Identification of the MN antigen as a diagnostic biomarker of cervical intraepithelial squamous and glandular neoplasia and cervical carcinomas. Am J Pathol 145(3):598–609
Liao SY, Aurelio ON, Jan K, Zavada J, Stanbridge EJ (1997) Identification of the MN/CA9 protein as a reliable diagnostic biomarker of clear cell carcinoma of the kidney. Cancer Res 57(14):2827–2831
Liao SY, Ivanov S, Ivanova A, Ghosh S, Cote MA, Keefe K, Coca-Prados M, Stanbridge EJ, Lerman MI (2003) Expression of cell surface transmembrane carbonic anhydrase genes CA9 and CA12 in the human eye: overexpression of CA12 (CAXII) in glaucoma. J Med Genet 40(4):257–261. https://doi.org/10.1136/jmg.40.4.257
Lou Y, McDonald PC, Oloumi A, Chia S, Ostlund C, Ahmadi A, Kyle A, Auf dem Keller U, Leung S, Huntsman D, Clarke B, Sutherland BW, Waterhouse D, Bally M, Roskelley C, Overall CM, Minchinton A, Pacchiano F, Carta F, Scozzafava A, Touisni N, Winum JY, Supuran CT, Dedhar S (2011) Targeting tumor hypoxia: suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors. Cancer Res 71(9):3364–3376. https://doi.org/10.1158/0008-5472.CAN-10-4261
Lounnas N, Rosilio C, Nebout M, Mary D, Griessinger E, Neffati Z, Chiche J, Spits H, Hagenbeek TJ, Asnafi V, Poulsen SA, Supuran CT, Peyron JF, Imbert V (2013) Pharmacological inhibition of carbonic anhydrase XII interferes with cell proliferation and induces cell apoptosis in T-cell lymphomas. Cancer Lett 333(1):76–88. https://doi.org/10.1016/j.canlet.2013.01.020
Lu C, Coradin M, Porter EG, Garcia BA (2020) Accelerating the field of epigenetic histone modification through mass spectrometry-based approaches. Mol Cell Proteomics 20:100006. https://doi.org/10.1074/mcp.R120.002257
Mahon BP, Bhatt A, Socorro L, Driscoll JM, Okoh C, Lomelino CL, Mboge MY, Kurian JJ, Tu C, Agbandje-McKenna M, Frost SC, McKenna R (2016) The structure of carbonic anhydrase IX Is adapted for low-pH catalysis. Biochemistry 55(33):4642–4653. https://doi.org/10.1021/acs.biochem.6b00243
Maupin CM, McKenna R, Silverman DN, Voth GA (2009) Elucidation of the proton transport mechanism in human carbonic anhydrase II. J Am Chem Soc 131(22):7598–7608. https://doi.org/10.1021/ja8091938
McDonald PC, Winum JY, Supuran CT, Dedhar S (2012) Recent developments in targeting carbonic anhydrase IX for cancer therapeutics. Oncotarget 3(1):84–97. https://doi.org/10.18632/oncotarget.422
McDonald PC, Chia S, Bedard PL, Chu Q, Lyle M, Tang L, Singh M, Zhang Z, Supuran CT, Renouf DJ, Dedhar S (2020) A phase 1 study of SLC-0111, a novel inhibitor of carbonic anhydrase IX, in patients with advanced solid tumors. Am J Clin Oncol 43(7):484–490. https://doi.org/10.1097/COC.0000000000000691
Mikulski RL, Silverman DN (2010) Proton transfer in catalysis and the role of proton shuttles in carbonic anhydrase. Biochim Biophys Acta 1804(2):422–426. https://doi.org/10.1016/j.bbapap.2009.08.003
Monti SM, Supuran CT, De Simone G (2012) Carbonic anhydrase IX as a target for designing novel anticancer drugs. Curr Med Chem 19(6):821–830
Monti SM, Supuran CT, De Simone G (2013) Anticancer carbonic anhydrase inhibitors: a patent review (2008–2013). Expert Opin Ther Pat 23(6):737–749. https://doi.org/10.1517/13543776.2013.798648
Muhammad E, Leventhal N, Parvari G, Hanukoglu A, Hanukoglu I, Chalifa-Caspi V, Feinstein Y, Weinbrand J, Jacoby H, Manor E, Nagar T, Beck JC, Sheffield VC, Hershkovitz E, Parvari R (2011) Autosomal recessive hyponatremia due to isolated salt wasting in sweat associated with a mutation in the active site of carbonic anhydrase 12. Hum Genet 129(4):397–405. https://doi.org/10.1007/s00439-010-0930-4
Noberini R, Robusti G, Bonaldi T (2021) Mass spectrometry-based characterization of histones in clinical samples: applications, progresses, and challenges. Febs J. https://doi.org/10.1111/febs.15707
Ondriskova E, Debreova M, Pastorekova S (2015) Tumor-associated carbonic anhydrases IX and XII. In: Supuran CT, De Simone G (eds) Carbonic anhydrases as biocatalysts—from theory to medical and industrial applications. Elsevier, Amsterdam, pp 169–206
Oosterwijk E, Ruiter DJ, Hoedemaeker PJ, Pauwels EK, Jonas U, Zwartendijk J, Warnaar SO (1986) Monoclonal antibody G 250 recognizes a determinant present in renal-cell carcinoma and absent from normal kidney. Int J Cancer 38(4):489–494
Opavsky R, Pastorekova S, Zelnik V, Gibadulinova A, Stanbridge EJ, Zavada J, Kettmann R, Pastorek J (1996) Human MN/CA9 gene, a novel member of the carbonic anhydrase family: structure and exon to protein domain relationships. Genomics 33(3):480–487
Pacchiano F, Carta F, McDonald PC, Lou Y, Vullo D, Scozzafava A, Dedhar S, Supuran CT (2011) Ureido-substituted benzenesulfonamides potently inhibit carbonic anhydrase IX and show antimetastatic activity in a model of breast cancer metastasis. J Med Chem 54(6):1896–1902. https://doi.org/10.1021/jm101541x
Parkkila S, Parkkila AK, Saarnio J, Kivela J, Karttunen TJ, Kaunisto K, Waheed A, Sly WS, Tureci O, Virtanen I, Rajaniemi H (2000) Expression of the membrane-associated carbonic anhydrase isozyme XII in the human kidney and renal tumors. J Histochem Cytochem 48(12):1601–1608. https://doi.org/10.1177/002215540004801203
Pastorekova S, Zavadova Z, Kostal M, Babusikova O, Zavada J (1992) A novel quasi-viral agent, MaTu, is a two-component system. Virology 187(2):620–626
Pilka ES, Kochan G, Oppermann U, Yue WW (2012) Crystal structure of the secretory isozyme of mammalian carbonic anhydrases CA VI: implications for biological assembly and inhibitor development. Biochem Biophys Res Commun 419(3):485–489. https://doi.org/10.1016/j.bbrc.2012.02.038
Popovic D, Vucic D, Dikic I (2014) Ubiquitination in disease pathogenesis and treatment. Nat Med 20(11):1242–1253. https://doi.org/10.1038/nm.3739
Potter C, Harris AL (2004) Hypoxia inducible carbonic anhydrase IX, marker of tumour hypoxia, survival pathway and therapy target. Cell Cycle 3(2):164–167
Proescholdt MA, Mayer C, Kubitza M, Schubert T, Liao SY, Stanbridge EJ, Ivanov S, Oldfield EH, Brawanski A, Merrill MJ (2005) Expression of hypoxia-inducible carbonic anhydrases in brain tumors. Neuro Oncol 7(4):465–475. https://doi.org/10.1215/S1152851705000025
Qian M, Yan F, Yuan T, Yang B, He Q, Zhu H (2020) Targeting post-translational modification of transcription factors as cancer therapy. Drug Discov Today 25(8):1502–1512. https://doi.org/10.1016/j.drudis.2020.06.005
Ray D, Cuneo KC, Rehemtulla A, Lawrence TS, Nyati MK (2015) Inducing oncoprotein degradation to improve targeted cancer therapy. Neoplasia 17(9):697–703. https://doi.org/10.1016/j.neo.2015.08.008
Roy A, Taraphder S (2007) Identification of proton-transfer pathways in human carbonic anhydrase II. J Phys Chem B 111(35):10563–10576. https://doi.org/10.1021/jp073499t
Safety study of SLC-0111 in subjects with advanced solid tumours (2014). https://clinicaltrials.gov/ct2/show/study/NCT02215850?term=SLC_0111&rank=1. Available via ClinicalTrials.gov. Accessed 13 Aug 2014
Saarnio J, Parkkila S, Parkkila AK, Haukipuro K, Pastorekova S, Pastorek J, Kairaluoma MI, Karttunen TJ (1998) Immunohistochemical study of colorectal tumors for expression of a novel transmembrane carbonic anhydrase, MN/CA IX, with potential value as a marker of cell proliferation. Am J Pathol 153(1):279–285. https://doi.org/10.1016/S0002-9440(10)65569-1
Sadoul K, Boyault C, Pabion M, Khochbin S (2008) Regulation of protein turnover by acetyltransferases and deacetylases. Biochimie 90(2):306–312. https://doi.org/10.1016/j.biochi.2007.06.009
Saenz-de-Santa-Maria I, Bernardo-Castineira C, Secades P, Bernaldo-de-Quiros S, Rodrigo JP, Astudillo A, Chiara MD (2017) Clinically relevant HIF-1alpha-dependent metabolic reprogramming in oropharyngeal squamous cell carcinomas includes coordinated activation of CAIX and the miR-210/ISCU signaling axis, but not MCT1 and MCT4 upregulation. Oncotarget 8(8):13730–13746. https://doi.org/10.18632/oncotarget.14629
Schwartz AL, Ciechanover A (2009) Targeting proteins for destruction by the ubiquitin system: implications for human pathobiology. Annu Rev Pharmacol Toxicol 49:73–96. https://doi.org/10.1146/annurev.pharmtox.051208.165340
Sheng Z, Wang X, Ma Y, Zhang D, Yang Y, Zhang P, Zhu H, Xu N, Liang S (2019) MS-based strategies for identification of protein SUMOylation modification. Electrophoresis 40(21):2877–2887. https://doi.org/10.1002/elps.201900100
Shin HJ, Rho SB, Jung DC, Han IO, Oh ES, Kim JY (2011) Carbonic anhydrase IX (CA9) modulates tumor-associated cell migration and invasion. J Cell Sci 124(Pt 7):1077–1087. https://doi.org/10.1242/jcs.072207
Silverman DN, McKenna R (2007) Solvent-mediated proton transfer in catalysis by carbonic anhydrase. Acc Chem Res 40(8):669–675. https://doi.org/10.1021/ar7000588
Stams T, Nair SK, Okuyama T, Waheed A, Sly WS, Christianson DW (1996) Crystal structure of the secretory form of membrane-associated human carbonic anhydrase IV at 2.8—a resolution. Proc Natl Acad Sci USA 93(24):13589–13594
Supuran CT (2012) Structure-based drug discovery of carbonic anhydrase inhibitors. J Enzyme Inhib Med Chem 27(6):759–772. https://doi.org/10.3109/14756366.2012.672983
Supuran CT (2016) How many carbonic anhydrase inhibition mechanisms exist? J Enzyme Inhib Med Chem 31(3):345–360. https://doi.org/10.3109/14756366.2015.1122001
Supuran CT (2020) Experimental carbonic anhydrase inhibitors for the treatment of hypoxic tumors. J Exp Pharmacol 12:603–617. https://doi.org/10.2147/JEP.S265620
Supuran CT, Di Fiore A, Alterio V, Monti SM, De Simone G (2010) Recent advances in structural studies of the carbonic anhydrase family: the crystal structure of human CA IX and CA XIII. Curr Pharm Des 16(29):3246–3254
Supuran CT, Alterio V, Di Fiore A, D’Ambrosio K, Carta F, Monti SM, De Simone G (2018) Inhibition of carbonic anhydrase IX targets primary tumors, metastases, and cancer stem cells: three for the price of one. Med Res Rev 38(6):1799–1836. https://doi.org/10.1002/med.21497
Svastova E, Zilka N, Zat’ovicova M, Gibadulinova A, Ciampor F, Pastorek J, Pastorekova S (2003) Carbonic anhydrase IX reduces E-cadherin-mediated adhesion of MDCK cells via interaction with beta-catenin. Exp Cell Res 290(2):332–345
Svastova E, Hulikova A, Rafajova M, Zat’ovicova M, Gibadulinova A, Casini A, Cecchi A, Scozzafava A, Supuran CT, Pastorek J, Pastorekova S (2004) Hypoxia activates the capacity of tumor-associated carbonic anhydrase IX to acidify extracellular pH. FEBS Lett 577(3):439–445. https://doi.org/10.1016/j.febslet.2004.10.043
Svastova E, Witarski W, Csaderova L, Kosik I, Skvarkova L, Hulikova A, Zatovicova M, Barathova M, Kopacek J, Pastorek J, Pastorekova S (2012) Carbonic anhydrase IX interacts with bicarbonate transporters in lamellipodia and increases cell migration via its catalytic domain. J Biol Chem 287(5):3392–3402. https://doi.org/10.1074/jbc.M111.286062
Swayampakula M, McDonald PC, Vallejo M, Coyaud E, Chafe SC, Westerback A, Venkateswaran G, Shankar J, Gao G, Laurent EMN, Lou Y, Bennewith KL, Supuran CT, Nabi IR, Raught B, Dedhar S (2017) The interactome of metabolic enzyme carbonic anhydrase IX reveals novel roles in tumor cell migration and invadopodia/MMP14-mediated invasion. Oncogene. https://doi.org/10.1038/onc.2017.219
Swietach P, Patiar S, Supuran CT, Harris AL, Vaughan-Jones RD (2009) The role of carbonic anhydrase 9 in regulating extracellular and intracellular ph in three-dimensional tumor cell growths. J Biol Chem 284(30):20299–20310. https://doi.org/10.1074/jbc.M109.006478
Tafreshi NK, Lloyd MC, Bui MM, Gillies RJ, Morse DL (2014) Carbonic anhydrase IX as an imaging and therapeutic target for tumors and metastases. Subcell Biochem 75:221–254. https://doi.org/10.1007/978-94-007-7359-2_12
Tu CK, Silverman DN, Forsman C, Jonsson BH, Lindskog S (1989) Role of histidine 64 in the catalytic mechanism of human carbonic anhydrase II studied with a site-specific mutant. Biochemistry 28(19):7913–7918
Tureci O, Sahin U, Vollmar E, Siemer S, Gottert E, Seitz G, Parkkila AK, Shah GN, Grubb JH, Pfreundschuh M, Sly WS (1998) Human carbonic anhydrase XII: cDNA cloning, expression, and chromosomal localization of a carbonic anhydrase gene that is overexpressed in some renal cell cancers. Proc Natl Acad Sci USA 95(13):7608–7613. https://doi.org/10.1073/pnas.95.13.7608
Turner JR, Odze RD, Crum CP, Resnick MB (1997) MN antigen expression in normal, preneoplastic, and neoplastic esophagus: a clinicopathological study of a new cancer-associated biomarker. Hum Pathol 28(6):740–744
Ulmasov B, Waheed A, Shah GN, Grubb JH, Sly WS, Tu C, Silverman DN (2000) Purification and kinetic analysis of recombinant CA XII, a membrane carbonic anhydrase overexpressed in certain cancers. Proc Natl Acad Sci USA 97(26):14212–14217. https://doi.org/10.1073/pnas.97.26.14212
van Wijk XM, Lawrence R, Thijssen VL, van den Broek SA, Troost R, van Scherpenzeel M, Naidu N, Oosterhof A, Griffioen AW, Lefeber DJ, van Delft FL, van Kuppevelt TH (2015) A common sugar-nucleotide-mediated mechanism of inhibition of (glycosamino)glycan biosynthesis, as evidenced by 6F-GalNAc (Ac3). FASEB J 29(7):2993–3002. https://doi.org/10.1096/fj.14-264226
Vermylen P, Roufosse C, Burny A, Verhest A, Bosschaerts T, Pastorekova S, Ninane V, Sculier JP (1999) Carbonic anhydrase IX antigen differentiates between preneoplastic malignant lesions in non-small cell lung carcinoma. Eur Respir J 14(4):806–811
von Neubeck B, Gondi G, Riganti C, Pan C, Parra Damas A, Scherb H, Erturk A, Zeidler R (2018) An inhibitory antibody targeting carbonic anhydrase XII abrogates chemoresistance and significantly reduces lung metastases in an orthotopic breast cancer model in vivo. Int J Cancer 143(8):2065–2075. https://doi.org/10.1002/ijc.31607
Waheed A, Sly WS (2017) Carbonic anhydrase XII functions in health and disease. Gene 623:33–40. https://doi.org/10.1016/j.gene.2017.04.027
Wang S, Yang F, Camp DG 2nd, Rodland K, Qian WJ, Liu T, Smith RD (2014) Proteomic approaches for site-specific O-GlcNAcylation analysis. Bioanalysis 6(19):2571–2580. https://doi.org/10.4155/bio.14.239
Whittington DA, Waheed A, Ulmasov B, Shah GN, Grubb JH, Sly WS, Christianson DW (2001) Crystal structure of the dimeric extracellular domain of human carbonic anhydrase XII, a bitopic membrane protein overexpressed in certain cancer tumor cells. Proc Natl Acad Sci USA 98(17):9545–9550. https://doi.org/10.1073/pnas.161301298
Whittington DA, Grubb JH, Waheed A, Shah GN, Sly WS, Christianson DW (2004) Expression, assay, and structure of the extracellular domain of murine carbonic anhydrase XIV: implications for selective inhibition of membrane-associated isozymes. J Biol Chem 279(8):7223–7228. https://doi.org/10.1074/jbc.M310809200
Wilex (2013) Ariser, adjuvant RENCAREX immunotherapy phase III trial to study efficacy in non metastatic RCC. https://www.heidelberg-pharma.com/wp-content/uploads/2013/02/20130226_WILEX-RENCAREX_subgroup-analysis_english.pdf. Accessed 15 July 2021
Wykoff CC, Beasley NJ, Watson PH, Turner KJ, Pastorek J, Sibtain A, Wilson GD, Turley H, Talks KL, Maxwell PH, Pugh CW, Ratcliffe PJ, Harris AL (2000) Hypoxia-inducible expression of tumor-associated carbonic anhydrases. Cancer Res 60(24):7075–7083
Wykoff CC, Beasley N, Watson PH, Campo L, Chia SK, English R, Pastorek J, Sly WS, Ratcliffe P, Harris AL (2001) Expression of the hypoxia-inducible and tumor-associated carbonic anhydrases in ductal carcinoma in situ of the breast. Am J Pathol 158(3):1011–1019. https://doi.org/10.1016/S0002-9440(10)64048-5
Xiao H, Suttapitugsakul S, Sun F, Wu R (2018) Mass Spectrometry-based chemical and enzymatic methods for global analysis of protein glycosylation. Acc Chem Res 51(8):1796–1806. https://doi.org/10.1021/acs.accounts.8b00200
Xu G, Jaffrey SR (2011) The new landscape of protein ubiquitination. Nat Biotechnol 29(12):1098–1100. https://doi.org/10.1038/nbt.2061
Zheng J, Avvaru BS, Tu C, McKenna R, Silverman DN (2008) Role of hydrophilic residues in proton transfer during catalysis by human carbonic anhydrase II. Biochemistry 47(46):12028–12036. https://doi.org/10.1021/bi801473w
Funding
MIUR: PRIN2017 (Grant 201744BN5T). MIUR-PON: “Ricerca e Innovazione” 2014−2020 (Grant MOLIM ONCOBRAIN LAB). Regione Campania: PO FESR 2014−2020 (Grant eMORFORAD).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no confict of interest.
Ethical approval
This article does not contain any studies with human participants or animals performed by any of the authors.
Consent for publication
All authors give their consent for publication.
Additional information
Handling editor: D. Tsikas.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Di Fiore, A., Supuran, C.T., Scaloni, A. et al. Post-translational modifications in tumor-associated carbonic anhydrases. Amino Acids 54, 543–558 (2022). https://doi.org/10.1007/s00726-021-03063-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00726-021-03063-y