Suppression of Ca2+ signaling enhances melanoma progression

Scott Gross, Robert Hooper, Dhanendra Tomar, Alexander P. Armstead, No'ad Shanas, Pranava Mallu, Hinal Joshi, Suravi Ray, Parkson Lee Gau Chong, Igor Astsaturov, Jeffrey M. Farma, Kathy Q. Cai, Kumaraswamy Naidu Chitrala, John W. Elrod, M. Raza Zaidi, Jonathan Soboloff

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

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 languageEnglish
Article numbere110046
Pages (from-to)e110046
JournalEMBO Journal
Volume41
Issue number19
DOIs
StatePublished - 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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