Carbonic Anhydrase IX as a Target for Renal Cell Carcinoma Therapy

Abstract

Renal cell carcinoma (RCC) is the third leading cause of death in genitourinary cancers, with a 126% increase in incidence over the past 60 years. The most common subtype of RCC, clear cell carcinoma, occurs in 7080% of RCC cases, most often caused by mutations in the Von-Hippel Lindau tumor suppressor gene. The VHL tumor suppressor protein acts to down-regulate Hypoxia Inducible Factor-1, a heterodimeric transcription factor which transactivates genes containing the Hypoxia Response Element (HRE) DNA sequences. Inactivation of this tumor suppressor leads to the stabilization of the HIF-1α subunit, driving the constituent expression of HRE-containing genes including several growth factors, and carbonic anhydrase IX. This carbonic anhydrase isoform is normally found in the gastrointestinal tract and absent in the kidney, however; it is over-expressed in clear cell RCC. Carbonic anhydrase is a ubiquitous enzyme, which maintains the acid-base balance of the cell, facilitates secretion of acid into the stomach and excretion of acid by the kidney, bone resorption, and production of cerebrospinal fluid. However, in clear cell RCC, the upregulation of CAIX has been shown to facilitate tumor progression and tumor cell invasiveness by decreasing the pH of the extracellular environment, leading to the degradation of the extracellular matrix. The specific expression pattern of CAIX makes it a useful biomarker in the diagnosis of clear cell RCC, and a strong candidate as a chemotherapeutic target. Current progress with this approach is discussed in this review.