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

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 Ca2+-permeating and Ca2+-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 Ca2+ 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.

Activation mechanisms and structural dynamics of STIM proteins

“…Tumour development, aggressiveness and poor prognosis of a wide variety of cancers is often also associated with an altered expression of STIM1 and STIM2, as described in detail in Tiffner et al (2022). For example, gastric and colorectal cancer tissues exhibit increased STIM1 expression in comparison with the respective non-cancerous tissues, which apparently promotes invasion and metastasis (Wang et al, 2015;Wen et al, 2016;Xia et al, 2016;Xu et al, 2016).…”

Identification of Glucosidase II that regulates STIM1 activation dynamics

“…Here, it engages with and activates Orai channels, precipitating Ca 2+ influx or SOCE 1,7,8,[11][12][13] . The implications of STIM1/Orai1 complex malfunctions are profound, implicated in a spectrum of diseases from severe combined immunodeficiency (SCID) to various muscular disorders and inflammatory conditions 1,[14][15][16][17] .…”

Synthetic Biology Meets Ca2+ Release-Activated Ca2+ Channel-Dependent Immunomodulation

“…In addition to the CRAC channels’ role in many immune cell functions, they are also potential drug targets for the treatment of various inflammatory reactions, allergic diseases [ 118 , 119 ], and many cancer types [ 20 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 ]. Several studies have confirmed that the genetic deletion or inhibition of CRAC channels hinders T cell and mast cell functions and diminishes inflammation of autoimmunity, transplant rejection, and asthma [ 119 ].…”