Abstract
Cancer is a leading cause of death worldwide, and its incidence is rising with numbers expected to increase 70% in the next two decades. The fact that current mainline treatments for cancer patients are accompanied by debilitating side effects prompts a growing demand for new therapies that not only inhibit growth and proliferation of cancer cells, but also control invasion and metastasis. One class of targets gaining international attention is the aquaporins, a family of membrane-spanning water channels with diverse physiological functions and extensive tissue-specific distributions in humans. Aquaporins−1,−2,−3,−4,−5,−8, and−9 have been linked to roles in cancer invasion, and metastasis, but their mechanisms of action remain to be fully defined. Aquaporins are implicated in the metastatic cascade in processes of angiogenesis, cellular dissociation, migration, and invasion. Cancer invasion and metastasis are proposed to be potentiated by aquaporins in boosting tumor angiogenesis, enhancing cell volume regulation, regulating cell-cell and cell-matrix adhesions, interacting with actin cytoskeleton, regulating proteases and extracellular-matrix degrading molecules, contributing to the regulation of epithelial-mesenchymal transitions, and interacting with signaling pathways enabling motility and invasion. Pharmacological modulators of aquaporin channels are being identified and tested for therapeutic potential, including compounds derived from loop diuretics, metal-containing organic compounds, plant natural products, and other small molecules. Further studies on aquaporin-dependent functions in cancer metastasis are needed to define the differential contributions of different classes of aquaporin channels to regulation of fluid balance, cell volume, small solute transport, signal transduction, their possible relevance as rate limiting steps, and potential values as therapeutic targets for invasion and metastasis.
Highlights
The first 13 aquaporins (AQP0–AQP12) have been divided into categories based on functional properties (Li and Wang, 2017)
Further work is needed to investigate whether mechanisms of AQP3- and AQP8facilitated cancer cell migration and invasion involve cell volume regulation, protrusion formation, cytoskeletal interaction, or other functional properties of the AQP channels that remain to be defined
This review focuses on selected AQP pharmacological agents that to date have been tested in models of cancer cell migration and metastasis (Table 2)
Summary
AquaporinsAquaporins (AQPs) are a family of water channels that include a subset of classes shown to mediate transport of glycerol, ions, and other molecules (Li and Wang, 2017). Enhances tumor cell migration and invasion by enabling rapid membrane protrusion formation via cell volume regulation and interaction with cytoskeletal dynamics Jiang (2009) found that knocking down AQP1 was associated with re-localization of actin in migrating HT20 colon cancer cells, and a reduction in the activity of actin regulatory factors RhoA and Rac. A PDZ domain in Lin-7 could mediate interaction with rhotekin protein, which inhibits Rho GTPase signaling that is involved in cell migration, invasion, and cytoskeletal reorganization (Sudo et al, 2006).
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