The role of carbonic anhydrase IX overexpression in kidney cancer.
Carbonic anhydrase IX (CA IX) is a membrane isoenzyme, the overexpression of which is associated with clear cell carcinoma of the kidney. Its overexpression is restricted mainly to cancer, as it is absent in corresponding normal tissues making it a potential cancer biomarker. Several recent studies have shown that CA IX, apart from its classical enzyme activity of reversibly hydrating carbon dioxide extracellularly to facilitate the net extrusion of protons from inside to outside the cell, it can also be a key player in the modulation of cell adhesion processes and participate in the regulation of cell proliferation in response to hypoxic environment to ultimately contribute to tumour progression. Here, we have shown that the sole tyrosine moiety of CA IX present in its intracellular domain can be phosphorylated in an epidermal growth factor dependent manner, suggesting that it can feed into the growth factor receptor dependent signalling pathways. Our studies suggest that the tyrosine phosphorylated CA IX can interact with the regulatory subunit of PI-3-Kinase, contributing to Akt activation. These studies have revealed a positive feed back loop that can form the basis of a vicious cycle that could contribute to the progression of clear cell renal carcinoma and poor prognosis. These studies show that CA IX signalling may be a part of both the hypoxia driven and hypoxia independent pathways that occur in the cancer cell. Finally, our studies emphasize the need for a more refined strategy using signal transduction therapeutics to inhibit the cell surface carbonic anhydrases for the management of this malignancy.
Dorai
Thambi
T
Comprehensive Cancer Center, Our Lady of Mercy Medical Center, New York Medical College, Bronx, NY 10466-2697, USA. tdorai@olmhs.org
Sawczuk
Ihor S
IS
Pastorek
Jaromir
J
Wiernik
Peter H
PH
Dutcher
Janice P
JP
D000951:Antigens, Neoplasm / Q000378:metabolism*; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D014408:Biomarkers, Tumor / Q000378:metabolism*; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D047468:Immunoprecipitation; D007680:Kidney Neoplasms / Q000378:metabolism*; D016296:Mutagenesis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D014162:Transfection
D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D019869:Phosphatidylinositol 3-Kinases; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases