Acid-sensing ion channels and downstream signalling in cancer cells: is there a mechanistic link?

Abstract

It is increasingly appreciated that the acidic microenvironment of a tumour contributes to its evolution and clinical outcomes. However, our understanding of the mechanisms by which tumour cells detect acidosis and the signalling cascades that it induces is still limited. Acid-sensing ion channels (ASICs) are sensitive receptors for protons; therefore, they are also candidates for proton sensors in tumour cells. Although in non-transformed tissue, their expression is mainly restricted to neurons, an increasing number of studies have reported ectopic expression of ASICs not only in brain cancer but also in different carcinomas, such as breast and pancreatic cancer. However, because ASICs are best known as desensitizing ionotropic receptors that mediate rapid but transient signalling, how they trigger intracellular signalling cascades is not well understood. In this review, we introduce the acidic microenvironment of tumours and the functional properties of ASICs, point out some conceptual problems, summarize reported roles of ASICs in different cancers, and highlight open questions on the mechanisms of their action in cancer cells. Finally, we propose guidelines to keep ASIC research in cancer on solid ground.

Potential Implications of Acid-Sensing Ion Channels ASIC2 and ASIC4 in Gonadal Differentiation of Dicentrarchus labrax Subjected to Water Temperature Increase during Gonadal Development

“…In fact, this effect was reported in A549 lung cancer cells, where acidosis (pH < 7.0) led to increased cell migration, proliferation, and metabolic activity [20]. It has been suggested that the reported increase in cell proliferation and migration was due to the ASIC-activation-induced Ca 2+ signaling [20]. Moreover, it has been shown that ASIC H(+)-gated are sensitive to temperature, which influences their kinetics [33].…”

“…Another potential role for tASIC2 and ASIC4 in the previtellogenic follicles is their implication in promoting the proliferation and differentiation of the granulosa layer. In fact, this effect was reported in A549 lung cancer cells, where acidosis (pH < 7.0) led to increased cell migration, proliferation, and metabolic activity [20]. It has been suggested that the reported increase in cell proliferation and migration was due to the ASIC-activation-induced Ca 2+ signaling [20].…”

“…A study investigating the sexually dimorphic behaviors of electric fish showed a sex-related difference in the expression of some ion channel types, including ASICs, suggesting a possible role of these channels in regulating gonadal function in fish or their involvement in neurogenomic mechanisms by which sex differences evolve [19]. It has been suggested that, among the ASICs, the ASIC2 and ASIC4 could have a potential role in promoting the proliferation and differentiation of the granulosa layer in the previtellogenic follicles [20]. It is important to know how sex is differentiated and determined in reared seabass as many male specimens have intratesticular oocytes, which indicate a certain sexual liability.…”