Through x-ray crystallography and kinase-inhibitor specificity profiling researchers reveal that curcumin, a natural 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 leads to inhibition of DYRK2 that impairs cell proliferation and reduces cancer burden.
But before turning to curcumin or turmeric supplements, the lead author cautions that curcumin alone may not be the answer.
"In general, curcumin is expelled from the body quite fast," said the author. "For curcumin to be an effective drug, it needs to be modified to enter the blood stream 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."
Writing in the journal of the Proceedings of the National Academy of Sciences, researchers report that curcumin binds to and inhibits DYRK2 leading to the impediment of the proteasome -- the cellular protein machinery that destroys unneeded or damaged proteins in cells -- which in turn reduces cancer in mice.
"Although curcumin has been studied for more than 250 years and its anti-cancer properties have been previously reported, no other group has reported a co-crystal structure of curcumin bound to a protein kinase target until now," said the first author on the study.
"The enzyme kinases IKK and GSK3 were thought to be the prime curcumin-targets that lead to anti-cancer 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."
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," said the co-senior author 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 suggest that targeting proteasome regulators (such as DYRK2) in combination with proteasome inhibitors may be a promising approach of anticancer therapy with less side-effects but further work is needed, said the author.
http://www.pnas.org/content/early/2018/07/05/1806797115
Latest News
Role of ECM in brain memory
By newseditor
Posted 13 May
All individuals with two co…
By newseditor
Posted 12 May
Autoantibody patterns in pa…
By newseditor
Posted 12 May
How brains convert sounds t…
By newseditor
Posted 12 May
Mice with traits of Tourett…
By newseditor
Posted 11 May
Other Top Stories
Capturing macrophages in action in lung alveoli
Read more
A nanobody that may prevent COVID-19 infection identified!
Read more
Gut fungi linked to higher Alzheimer's risk can be treated with ket…
Read more
Mini proteins to treat COVID-19
Read more
Middle-aged individuals may be in a perpetual state of H3N2 flu vir…
Read more
Protocols
Mime-seq 2.0: a method to s…
By newseditor
Posted 13 May
Improved detection of DNA r…
By newseditor
Posted 09 May
Single-cell adhesive profil…
By newseditor
Posted 07 May
Parasympathetic neurons der…
By newseditor
Posted 07 May
Non-invasive measurements o…
By newseditor
Posted 05 May
Publications
Antigen-specific Fab profil…
By newseditor
Posted 12 May
Differential representation…
By newseditor
Posted 12 May
Glucose hypometabolism prom…
By newseditor
Posted 12 May
Organellophagy regulates ce…
By newseditor
Posted 12 May
Decoding mitochondria's rol…
By newseditor
Posted 11 May
Presentations
Hydrogels in Drug Delivery
By newseditor
Posted 12 Apr
Lipids
By newseditor
Posted 31 Dec
Cell biology of carbohydrat…
By newseditor
Posted 29 Nov
RNA interference (RNAi)
By newseditor
Posted 23 Oct
RNA structure and functions
By newseditor
Posted 19 Oct
Posters
A chemical biology/modular…
By newseditor
Posted 22 Aug
Single-molecule covalent ma…
By newseditor
Posted 04 Jul
ASCO-2020-HEALTH SERVICES R…
By newseditor
Posted 23 Mar
ASCO-2020-HEAD AND NECK CANCER
By newseditor
Posted 23 Mar
ASCO-2020-GENITOURINARY CAN…
By newseditor
Posted 23 Mar