Curcumin Shown to Inhibit DYRK2 and Reduce Cancer Burden
University of California San Diego School of Medicine scientists, in collaboration with colleagues at Peking University and Zhejiang University, report that curcumin, a naturally occurring chemical compound found in the spice turmeric, binds to the kinase enzyme dual-specificity tyrosine-regulated kinase 2 (DYRK2) at the atomic level.
This previously unreported biochemical interaction of curcumin, discovered using x-ray crystallography and kinase-inhibitor specificity profiling, leads to inhibition of DYRK2 that impairs cell proliferation and reduces cancer burden. The study (“Ancient drug curcumin impedes 26S proteasome activity by direct inhibition of dual-specificity tyrosine-regulated kinase 2”) is published in PNAS.
“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 co-crystal 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,” write the investigators.
“In a breast cancer [mouse] 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.”
But before turning to curcumin or turmeric supplements, Sourav Banerjee, Ph.D., UC San Diego School of Medicine postdoctoral scholar, cautions that curcumin alone may not be the answer.
“In general, curcumin is expelled from the body quite fast,” says Dr. Banerjee. “For curcumin to be an effective drug, it needs to be modified to enter the bloodstream and stay in the body long enough to target the cancer. Owing to various chemical drawbacks, curcumin on its own may not be sufficient to completely reverse cancer in human patients.
“Although curcumin has been studied for more than 250 years and its anticancer properties have been previously reported, no other group has reported a co-crystal structure of curcumin bound to a protein kinase target until now. Because of their work on the crystallography, our collaborators at Peking University, Chenggong Ji and Junyu Xiao, helped us to visualize the interaction between curcumin and DYRK2.
“The enzyme kinases IKK and GSK3 were thought to be the prime curcumin-targets that lead to anticancer effect but the co-crystal structure of curcumin with DYRK2 along with a 140-panel kinase inhibitor profiling reveal that curcumin binds strongly to the active site of DYRK2, inhibiting it at a level that is 500 times more potent than IKK or GSK3.”
Working with Jack E. Dixon, Ph.D., distinguished professor of pharmacology, cellular and molecular medicine, chemistry and biochemistry at UC San Diego, Dr. Banerjee and his team have been looking for regulators of proteasomes to inhibit tumor formation by proteasome-addicted cancers like triple-negative breast cancer (TNBC) and the plasma cell malignancy called multiple myeloma.
Using biochemical, mouse cancer models and cellular models the team found that curcumin is a selective inhibitor of DYRK2 and that this novel molecular target has promising anticancer potential for not only chemo-sensitive but also proteasome inhibitor-resistant/adapted cancers.
“Our 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 hard-to-treat triple-negative breast cancer and multiple myeloma treatment,” says Dr. Dixon, who was co-senior author with Zhejiang University’s Xing Guo, Ph.D., on the paper. “Our primary focus is to develop a chemical compound that can target DYRK2 in patients with these cancers.”
DYRK2 depletion impairs proteasome activity and exhibits slower cancer proliferation rates and significantly reduced tumor burden in mouse models. In combination with the FDA-approved multiple myeloma drug, carfilzomib, curcumin induced a much higher cancer cell death while normal non-cancerous cells were less affected.
This suggests that targeting proteasome regulators (such as DYRK2) in combination with proteasome inhibitors may be a promising approach to anticancer therapy with fewer side-effects but further work is needed, according to Dr. Banerjee.