2-Methoxyestradiol and its derivatives inhibit store-operated Ca2+ entry in T cells: identification of a new and potent inhibitor

Journal article

T cell activation starts with formation of second messengers that release Ca²⁺ from the endoplasmic reticulum (ER) and thereby activate store-operated Ca²⁺ entry (SOCE), one of the essential signals for T cell activation. Recently, the steroidal 2-methoxyestradiol was shown to inhibit nuclear translocation of the nuclear factor of activated T cells (NFAT). We therefore investigated 2-methoxyestradiol for inhibition of Ca²⁺ entry in T cells, screened a library of 2-methoxyestradiol analogues, and characterized the derivative 2-ethyl-3-sulfamoyloxy-17β-cyanomethylestra-1,3,5(10)-triene (STX564) as a novel, potent and specific SOCE inhibitor. STX564 inhibits Ca²⁺ entry via SOCE without affecting other ion channels and pumps involved in Ca²⁺ signaling in T cells. Downstream effects such as cytokine expression and cell proliferation were also inhibited by both 2-methoxyestradiol and STX564, which has potential as a new chemical biology tool.

Authors: Löhndorf, A; Hosang, L; Dohle, W; Odoardi, F; Waschkowski, S-A

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Elsevier
• Journal: Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
• Volume: 1868
• Issue: 6
• Article number: 118988
• Publication date: 2021-02-10
• Acceptance date: 2021-02-04
• DOI: 10.1016/j.bbamcr.2021.118988
• EISSN: 1879-2596
• ISSN: 0167-4889
• Pmid: 33581218
• Language: English
• Keywords: Ca(2+) signaling; store-operated Ca(2+) entry; FFR; T cell activation; ORAI inhibitor