The role of Orai–STIM calcium channels in melanocytes and melanoma

• Published in: The Journal of physiology Vol. 594; no. 11; pp. 2825 - 2835
• Main Authors: Stanisz, Hedwig, Vultur, Adina, Herlyn, Meenhard, Roesch, Alexander, Bogeski, Ivan
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.06.2016; John Wiley and Sons Inc
• Subjects: Animals; Calcium; Cancer; Cellular and Molecular Physiology; Humans; Melanocytes - metabolism; Melanocytes - pathology; Melanoma; Melanoma - metabolism; Melanoma - pathology; ORAI1 Protein - physiology; Rodents; Signalling Pathways; Stromal Interaction Molecule 1 - physiology; Symposium Review; Symposium section reviews: Molecular and cellular mechanisms in health and disease
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/JP271141

Calcium signalling within normal and cancer cells regulates many important cellular functions such as migration, proliferation, differentiation and cytokine secretion. Store operated Ca2+ entry (SOCE) via the Ca2+ release activated Ca2+ (CRAC) channels, which are composed of the plasma membrane based Orai channels and the endoplasmic reticulum stromal interaction molecules (STIMs), is a major Ca2+ entry route in many cell types. Orai and STIM have been implicated in the growth and metastasis of multiple cancers; however, while their involvement in cancer is presently indisputable, how Orai–STIM‐controlled Ca2+ signals affect malignant transformation, tumour growth and invasion is not fully understood. Here, we review recent studies linking Orai–STIM Ca2+ channels with cancer, with a particular focus on melanoma. We highlight and examine key molecular players and the signalling pathways regulated by Orai and STIM in normal and malignant cells, we expose discrepancies, and we reflect on the potential of Orai–STIMs as anticancer drug targets. Finally, we discuss the functional implications of future discoveries in the field of Ca2+ signalling. The functional role of Orai–STIM Ca2+ channels in melanoma. Activation of surface receptors leads to depletion of endoplasmic reticulum (ER) Ca2+ stores and a subsequent assembly of the Orai–STIM channel complex which facilitates entry of Ca2+ across the plasma membrane and an increase in cytosolic Ca2+ concentration. Activation of Orai–STIM channels positively correlates with expression and enzymatic activity of MITF, PKB/AKT, ERK and Src and negatively with JARID1B and Brn2. Moreover, PKC and Wnt5a can inhibit channel activity directly by phosphorylating the channel. In melanoma, this store‐operated Ca2+ entry controls crucial cellular functions such as proliferation, migration and invasion.