Suppression of Ca²⁺ signaling enhances melanoma progression

Abstract

Ca 2+ 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 Ca 2+ signals can lead to pathological phenotypes, including cancer progression. However, given the highly context-specific nature of Ca 2+ -dependent changes in cell function, delineation of its role in cancer has been a challenge. Hence, the role of store-operated Ca 2+ entry (SOCE) in melanoma metastasis is still not fully elucidated. To address this, we examined UVdependent 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. CHAPTER 1 INTRODUCTION Part 1: Calcium I. Ca 2+ signal generation: Ca 2+ signals are generated in response to a wide variety of autocrine, paracrine, hormonal, neurocrine and environmental factors. Here, we will briefly discuss some of the major underlying approaches that cells use to generate Ca 2+ responses. A. Receptor-mediated control of Ca 2+ signals G-Protein Coupled Receptor (GPCR) and Receptor Tyrosine Kinase (RTK) families are widely expressed and facilitate Ca 2+ responses in virtually all cell types through phospholipase C (PLC). Briefly, as shown in Figure 1-1, when Gαq-coupled GPCRs (driving PLCβ activation) or RTKs with PLCγ docking sites are activated, PLC hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) into Inositol Trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 diffuses within the cell towards the ER where it encounters InsP3 Receptors (InsP3Rs), ER-localized Ca 2+ channels that mediate ER Ca 2+ release. The resultant ER Ca 2+ depletion leads to a highly conserved process known as store-operated Ca 2+ entry (SOCE) (4-7). SOCE is initiated by Stromal Interaction Molecule (STIM), a single pass membrane protein that acts as an Endoplasmic Reticulum (ER) Ca 2+ sensor, responding to ER Ca 2+ depletion by translocating within the ER towards the plasma membrane (PM) where it binds to and activates members of the Orai family of Ca 2+ -selective channels (6, 8). STIM1 and Orai1 serve as the predominant mediators of SOCE in most cell types (8), although the other members of the STIM and Orai families can function analogously, although with distinct characteristics. For example, a decrease

The sun, cholesterol and Orai1 conspire in melanoma

“…Increased Orai1‐mediated Ca 2+ influx may promote tumor induction, while decreased Orai1 activity may promote metastasis. Because CHL concentration is elevated in many solid organ tumors, further investigating these mechanisms in other malignancies could therefore expand the relevance of Gross et al (2022) findings.…”

“…To search for potential consequences of reduced SOCE activity that might promote invasive melanoma, Gross et al (2022) further analyzed the transcriptomes of UV‐transformed invasive and noninvasive melanoma cells to identify genes associated with both SOCE suppression and invasiveness. Both were associated with marked upregulation of genes involved in metabolic functions, particularly glucose uptake.…”

“…Reduced MCU activity was associated with enhanced antioxidants that is necessary and sufficient for the enhanced melanoma invasiveness. Reduced MCU activity increases Ca 2+ at the mouth of Orai1 to decrease its activity (Prakriya & Lewis, 2015), which may contribute to the reduced Orai1 activity reported by Gross et al (2022). Thus, the findings of Gross et al (2022) and Stejerean‐Todoran et al (2022) provide two cytoplasmic Ca 2+ related and likely linked targets to be considered for developing a new therapy for invasive melanoma.…”

“…However, the role of Ca 2+ influx in UV radiation‐triggered malignant transformation is not well‐defined. A study published in this issue of the EMBO Journal by the group of Jonathan Soboloff (Gross et al , 2022) reports a novel and intricate pathway that confers metastatic potential to transformed melanocytes (Fig 1).…”

“…The sun, cholesterol and Orai1 conspire in melanoma Woo Young Chung & Shmuel Muallem * How does skin cancer become metastatic? A recent study by Gross et al (2022) reports a novel pathway by which UV radiation acts on cholesterol biosynthesis to control Ca 2+ influx by Orai1, causing protein O-GlcNAcylation that promotes transformation to invasive melanoma.…”