Suppression of Ca2+ Signaling Enhances Melanoma Progression
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. Hence, the role of store-operated Ca2+ entry (SOCE) in melanoma metastasis is still not fully elucidated. To address this, we examined UV-dependent metastasis, revealing a critical role for SOCE suppression. As previous literature demonstrated a role for cholesterol (CHL) in melanoma progression, our investigations corroborate this revealing UV-induced CHL biosynthesis as a critical mediator for UV-induced SOCE suppression and subsequent metastasis. However, SOCE suppression alone was both necessary and sufficient for metastasis to occur. Further, SOCE suppression facilitated UV-dependent differences in gene expression associated with increased invasion through altered glucose utilization. Functional analyses further establish 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 CHL dependent low SOCE. Invasiveness could be reversed with either CHL biosynthesis inhibitors, pharmacological inhibition of terminal glycosylation enzyme, OGT, or pharmacological SOCE potentiation. In parallel, we demonstrate that Geranylgeranylpyrophosphate (GGPP) can function as a novel SOCE inhibitor either by saturation or prevention of transfer to membrane proteins; both of which lead to GGPP accumulation in the cytosol. Collectively, we provide evidence that Ca2+ signals can block invasive behavior, and suppression of these signals promotes invasion and metastasis.
Biology, Calcium, Cancer, Cholesterol, Glycosylation, Ion channels, Melanoma
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