Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 32, Pages 8155-8160Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1806797115
Keywords
triple-negative breast cancer; multiple myeloma; proteasome inhibitor; kinase specificity profiling; DYRK
Categories
Funding
- National Key Research and Development Program of China [2017YFA0505200, 2016YFC0906000]
- NIH [DK018849-41, DK018024-43]
- Mary Kay Ash Breast Cancer [047.16]
- Natural Science Foundation of China [31671391]
- Zhejiang Natural Science Foundation [LR18C050001]
- University of California at San Diego NIH/National Cancer Institute Cancer Training Grant [T32 CA009523]
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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 265 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 265 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.
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