Abstract
The anti-proliferative activity of dietary flavonoid fisetin has been validated in various cancer models. Establishing its precise mechanism of action has proved somewhat challenging given the multiplicity of its targets. We demonstrated that YB-1 promotes epithelial-to-mesenchymal transition and its inhibition suppressed tumor cell proliferation and invasion. The p90 ribosomal S6 kinase (RSK), an important ERK effector, activates YB-1 to drive melanoma growth. We found that fisetin treatment of monolayer/3-D melanoma cultures resulted in YB-1 dephosphorylation and reduced transcript levels. In parallel, fisetin suppressed mesenchymal markers and matrix-metalloproteinases in melanoma cells. Data from cell-free/cell-based systems indicated that fisetin inhibited RSK activity through binding to the kinase. Affinity studies for RSK isoforms evaluated stronger interaction for RSK2 than RSK1. Competition assays performed to monitor binding responses revealed that YB-1 and RSK2 do not compete, rather binding of fisetin to RSK2 promotes its binding to YB-1. Fisetin suppressed YB-1/RSK signaling independent of its effect on ERK, and reduced MDR1 levels. Comparable efficacy of fisetin and vemurafenib for inhibiting melanoma growth was noted albeit through divergent modulation of ERK. Our studies provide insight into additional modes of regulation through which fisetin interferes with melanoma growth underscoring its potential therapeutic efficacy in disease progression.
Highlights
5 million patients are diagnosed with skin cancer in the United States, each year
We examined the effect of fisetin on endogenous levels of YB-1 in highly aggressive BRAF mutant melanoma cells
We had previously shown that forced expression of YB-1 promoted epithelial-mesenchymal transition (EMT) in prostate cancer that was effectively inhibited by fisetin[21]
Summary
5 million patients are diagnosed with skin cancer in the United States, each year. Fisetin treatment (0–80 μM:[24] h) to A375 and 451Lu melanoma cells resulted in a dose-dependent decrease in YB-1 phosphorylation concomitant with downregulation of total protein levels, as assessed by western blot and immunocytochemical analysis Regardless, fisetin treatment abrogated RSK phosphorylation at threonine359/serine[363] and decreased MDR1 levels in YB-1 overexpressing WM35 melanoma cells
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
