Role of Aquaporin1 in Diseases and Drug Discovery

Abstract

Aquaporin-1 is a dual water and ion channel that mediates transport of water, glycerol, ions, and small molecules. AQP1 has reported to involve in a wide range of physiological functions and human diseases. At the cellular level, AQP1 promoted water movement across cell plasma membrane facilitates transepithelial fluid transport, cell migration, and cell volume change. Genetic knockdown studies of AQP1 showed impairment in fluid transportations, suggesting that pharmacologically targeting AQP1 can alter water movement in cell, which could be a useful approach for AQP1 related diseases. This thesis is aims to discover new pharmacological agents for both AQP1 water and ion channel, and test these agents in two diseases, cancer and sickle cell diseases. The first part of this thesis investigated the role of AQP1 in cancer migration. AQP1 expression is upregulated in many aggressive cancers, including colon, breast, and brain cancer. Overexpression of AQP1 in cancer is thought to facilitate cell migration, invasion and metastasis. Work here discovered a novel AQP1 ion channel blocker, 5-hydroxymethyl-furfural (5HMF). Results here showed that 5HMF impaired AQP1 ion channel conductance in AQP1-expressing oocytes, and significantly reduced cell migration and invasion in AQP1-expressing cancer cell lines. Work here also showed that KeenMind extracts from Bacopa monnieri blocked the AQP1 water channel and slowdown cancer cell migration in AQP1-expressing cell line. Both of the pharmacological agents did not induce any toxic effect to tested cell lines. In the last part of this thesis, the AQP1 ion channel was investigated for its role in sick cell disease. Mutated haemoglobin in red blood cell undergoes polymerization in deoxygenated conditions. Several novel anti-sickle agents were tested its effect on AQP1 ion channel activity. Work here showed that high efficacy agents impaired AQP1 ion channel activity, while low efficacy agents had no effect of AQP1 ion channel, suggesting that AQP1 ion channel is one of the factor that facilitate sickle cell formation. Work in this thesis paves the way for developing an AQP1-based therapy and revealing a possible role of AQP1 ion channel in sickle cell diseases.