CRAC and SK Channels: Their Molecular Mechanisms Associated with Cancer Cell Development

SIMPLE SUMMARY: Cell fate is ultimately determined by the precisely coordinated action of the Ca(2+)-signaling machinery. During carcinogenesis, Ca(2+) signaling is significantly remodeled due to mutations and/or ectopic expression. Here, we summarize current knowledge on how alterations in Ca(2+) signaling contribute to the development of different cancer hallmarks. Emphasis is placed on the structure/function relationship of the well-studied store-operated Ca(2+) channel, i.e., Orai1, and the Ca(2+)-activated K(+) channel, i.e., SK3, alongside their individual and joint roles in cancer. This review lays out the current state of knowledge of Ca(2+)-signaling effectors and proteins as potential targets for the treatment of certain cancer types, with Orai1 and SK3 presented as emerging therapeutic targets. ABSTRACT: Cancer represents a major health burden worldwide. Several molecular targets have been discovered alongside treatments with positive clinical outcomes. However, the reoccurrence of cancer due to therapy resistance remains the primary cause of mortality. Endeavors in pinpointing new markers as molecular targets in cancer therapy are highly desired. The significance of the co-regulation of Ca(2+)-permeating and Ca(2+)-regulated ion channels in cancer cell development, proliferation, and migration make them promising molecular targets in cancer therapy. In particular, the co-regulation of the Orai1 and SK3 channels has been well-studied in breast and colon cancer cells, where it finally leads to an invasion-metastasis cascade. Nevertheless, many questions remain unanswered, such as which key molecular components determine and regulate their interplay. To provide a solid foundation for a better understanding of this ion channel co-regulation in cancer, we first shed light on the physiological role of Ca(2+) and how this ion is linked to carcinogenesis. Then, we highlight the structure/function relationship of Orai1 and SK3, both individually and in concert, their role in the development of different types of cancer, and aspects that are not yet known in this context.