The Water Channels, New Druggable Targets to Combat Cancer Cell Survival,Invasiveness and Metastasis

Cell viability and motility are critical for cancer progression. Among a plethora of mechanisms that regulate these phenotypes, the balance of water and monovalent metal cations plays a pivotal role in the dynamics of focal contacts and cytoskeletal rearrangements at the cell's leading edge. Furthermore, cell survival requires the optimal concentration of water and solutes. This balance is largely maintained by aquaporins (AQPs), a family of 13 small integral plasma membrane proteins whose major function is the transport of water and small solutes across the plasma membrane. We review the recent knowledge about the role of AQPs in cell migration, survival, tumor angiogenesis and metastasis with the focus on therapeutic possibilities to prevent these clinically unfavourable events. The review discusses the inhibition of AQP expression and/or AQP-mediated water influx by acetazolamide, cyclophosphamide, topiramate, thiopental, phenobarbital and propofol. Down-regulation of water transport by these drugs affects cancer cell migration and metastasis. We conclude that AQPs can be considered a point where the mechanisms of survival and motility converge. Therapeutic targeting of AQPs may thus be advantageous for blocking the mechanism common for a number of key cancer phenotypes.