Calcium channels and pumps in cancer: changes and consequences

Abstract

Increases in intracellular free Ca(2+) play a major role in many cellular processes. The deregulation of Ca(2+) signaling is a feature of a variety of diseases, and modulators of Ca(2+) signaling are used to treat conditions as diverse as hypertension to pain. The Ca(2+) signal also plays a role in processes important in cancer, such as proliferation and migration. Many studies in cancer have identified alterations in the expression of proteins involved in the movement of Ca(2+) across the plasma membrane and subcellular organelles. In some cases, these Ca(2+) channels or pumps are potential therapeutic targets for specific cancer subtypes or correlate with prognosis.

FIGURE 1.

ORAI1 regulates processes important for cancer cell proliferation, migration, and apoptosis. A, in MCF-7 human breast cancer cells, SPCA2 partially localizes to the plasma membrane and interacts with ORAI1 to mediate store-independent Ca²⁺ influx. This is associated with phosphorylation of ERK1/2, nuclear translocation of NFAT, and increased cell proliferation (39). B, silencing of ORAI1 or STIM1 in MDA-MB-231 human breast cancer cells reduces store-operated Ca²⁺ influx and is associated with reduced focal adhesion turnover, cell migration, and metastasis formation in vivo. Expression of constitutively active Ras or Rac in these cells partially rescues impaired focal adhesion turnover and cell migration induced by inhibition of store-operated Ca²⁺ entry, implicating possible roles for these small GTPases in Ca²⁺-dependent cell migration (39). C, in LNCaP human prostate cancer cells, ORAI1 expression is regulated by the androgen receptor (AR), and ORAI1 silencing is associated with resistance to thapsigargin (TG)-, TNFα-, cisplatin-, and oxaliplatin-induced apoptosis (43). In A and B (black), ORAI1 expression may promote carcinogenesis; in C (red), ORAI1 expression may inhibit carcinogenesis (i.e. promote apoptosis). IP₃Rs, inositol 1,4,5-trisphosphate receptors.