Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2018 Aug 7;115(32):8155-8160. doi: 10.1073/pnas.1806797115. Epub 2018 Jul 9.

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

Author information

1
Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093-0721.
2
The State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, 100871 Beijing, China.
3
Division of the Department of Radiation Oncology, The University of Iowa, Iowa City, IA 52242-1181.
4
Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093-0721; jedixon@ucsd.edu xguo@zju.edu.cn.
5
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093.
6
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093.
7
The Life Sciences Institute, Zhejiang University, 310058 Hangzhou, China jedixon@ucsd.edu xguo@zju.edu.cn.

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.

KEYWORDS:

DYRK; kinase specificity profiling; multiple myeloma; proteasome inhibitor; triple-negative breast cancer

PMID:
29987021
PMCID:
PMC6094102
DOI:
10.1073/pnas.1806797115
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no conflict of interest.

Publication types, MeSH terms, Substances, Secondary source ID, Grant support

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center