Suppression of Ca2+ signaling enhances melanoma progression.

The role of store-operated Ca2+ entry (SOCE) in melanoma metastasis is highly controversial. To address this, we here examined UV-dependent metastasis, revealing a critical role for SOCE suppression in melanoma progression. UV-induced cholesterol biosynthesis was critical for UV-induced SOCE suppression and subsequent metastasis, although SOCE suppression alone was both necessary and sufficient for metastasis to occur. Further, SOCE suppression was responsible for UV-dependent differences in gene expression associated with both increased invasion and reduced glucose metabolism. Functional analyses further established that increased glucose uptake leads to a metabolic shift towards biosynthetic pathways critical for melanoma metastasis. Finally, examination of fresh surgically isolated human melanoma explants revealed cholesterol biosynthesis-dependent reduced SOCE. Invasiveness could be reversed with either cholesterol biosynthesis inhibitors or pharmacological SOCE potentiation. Collectively, we provide evidence that, contrary to current thinking, Ca2+ signals can block invasive behavior, and suppression of these signals promotes invasion and metastasis.

Ca2+ as a therapeutic target in cancer.

Ca2+ is a ubiquitous and dynamic second messenger molecule that is induced by many factors including receptor activation, environmental factors, and voltage, leading to pleiotropic effects on cell function including changes in migration, metabolism and transcription. As such, it is not surprising that aberrant regulation of Ca2+ signals can lead to pathological phenotypes, including cancer progression. However, given the highly context-specific nature of Ca2+-dependent changes in cell function, delineation of its role in cancer has been a challenge. Herein, we discuss the distinct roles of Ca2+ signaling within and between each type of cancer, including consideration of the potential of therapeutic strategies targeting these signaling pathways.