Abstract
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.
Original language | English |
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Article number | e110046 |
Pages (from-to) | e110046 |
Journal | EMBO Journal |
Volume | 41 |
Issue number | 19 |
DOIs | |
State | Published - Sep 4 2022 |
Keywords
- Calcium Channels/metabolism
- Calcium Signaling
- Calcium/metabolism
- Cholesterol
- Glucose
- Humans
- Melanoma/genetics
- ORAI1 Protein/metabolism
- Stromal Interaction Molecule 1/metabolism
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Fox Chase Cancer Center: Melanoma Cells Metastasize When Key Calcium Entry Pathway is Suppressed, Study Shows
09/27/22 → 09/28/22
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