Ancient drug curcumin impedes 26S proteasome activity by direct inhibition of dual-specificity tyrosine-regulated kinase 2

Sourav Banerjee, Chenggong Ji, Joshua E. Mayfield, Apollina Goel, Junyu Xiao, Jack E. Dixon (Lead / Corresponding author), Xing Guo (Lead / Corresponding author)

Research output: Contribution to journalArticle

38 Citations (Scopus)
41 Downloads (Pure)

Abstract

Curcumin, the active ingredient in Curcuma longa, has been in medicinal use since ancient times. However, the therapeutic targets and signaling cascades modulated by curcumin have been enigmatic despite extensive research. Here we identify dual-specificity tyrosine-regulated kinase 2 (DYRK2), a positive regulator of the 26S proteasome, as a direct target of curcumin. Curcumin occupies the ATP-binding pocket of DYRK2 in the cocrystal structure, and it potently and specifically inhibits DYRK2 over 139 other kinases tested in vitro. As a result, curcumin diminishes DYRK2-mediated 26S proteasome phosphorylation in cells, leading to reduced proteasome activity and impaired cell proliferation. Interestingly, curcumin synergizes with the therapeutic proteasome inhibitor carfilzomib to induce apoptosis in a variety of proteasome-addicted cancer cells, while this drug combination exhibits modest to no cytotoxicity to noncancerous cells. In a breast cancer xenograft model, curcumin treatment significantly reduces tumor burden in immunocompromised mice, showing a similar antitumor effect as CRISPR/Cas9-mediated DYRK2 depletion. These results reveal an unexpected role of curcumin in DYRK2-proteasome inhibition and provide a proof-of-concept that pharmacological manipulation of proteasome regulators may offer new opportunities for anticancer treatment.

Original languageEnglish
Pages (from-to)8155-8160
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number32
Early online date9 Jul 2018
DOIs
Publication statusPublished - 7 Aug 2018

Keywords

  • DYRK
  • kinase specificity profiling
  • multiple myeloma
  • Proteasome inhibitor
  • Triple-negative breast cancer

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