Dietary flavonoid fisetin binds to β-tubulin and disrupts microtubule dynamics in prostate cancer cells.

Abstract

Microtubule targeting based therapies have revolutionized cancer treatment; however, resistance and side effects remain a major limitation. Therefore, novel strategies that can overcome these limitations are urgently needed. We made a novel discovery that fisetin, a hydroxyflavone, is a microtubule stabilizing agent. Fisetin binds to tubulin and stabilizes microtubules with binding characteristics far superior than paclitaxel. Surface plasmon resonance and computational docking studies suggested that fisetin binds to β-tubulin with superior affinity compared to paclitaxel. Fisetin treatment of human prostate cancer cells resulted in robust up-regulation of microtubule associated proteins (MAP)-2 and -4. In addition, fisetin treated cells were enriched in α-tubulin acetylation, an indication of stabilization of microtubules. Fisetin significantly inhibited PCa cell proliferation, migration, and invasion. Nudc, a protein associated with microtubule motor dynein/dynactin complex that regulates microtubule dynamics, was inhibited with fisetin treatment. Further, fisetin treatment of a P-glycoprotein overexpressing multidrug-resistant cancer cell line NCI/ADR-RES inhibited the viability and colony formation. Our results offer in vitro proof-of-concept for fisetin as a microtubule targeting agent. We suggest that fisetin could be developed as an adjuvant for treatment of prostate and other cancer types.

• Authors: Eiman Mukhtar, Vaqar Mustafa Adhami, Mario Sechi, Hasan Mukhtar
• Journal: Cancer letters (Cancer Lett) Vol. 367 Issue 2 Pg. 173-83 (Oct 28 2015) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 26235140 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Cell Cycle Proteins
• Flavonoids
• Flavonols
• MAP2 protein, human
• MAP4 protein, human
• Microtubule-Associated Proteins
• NUDC protein, human
• Nuclear Proteins
• Tubulin
• Tubulin Modulators
• fisetin
• Paclitaxel

Topics

• Acetylation
• Animals
• Binding Sites
• Cell Cycle Proteins (metabolism)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Flavonoids (chemistry, metabolism, pharmacology)
• Flavonols
• Male
• Microtubule-Associated Proteins (metabolism)
• Microtubules (drug effects, metabolism)
• Molecular Docking Simulation
• Neoplasm Invasiveness
• Nuclear Proteins (metabolism)
• Paclitaxel (pharmacology)
• Prostatic Neoplasms (genetics, metabolism, pathology)
• Protein Binding
• Protein Conformation
• Protein Processing, Post-Translational
• Protein Stability
• Signal Transduction (drug effects)
• Surface Plasmon Resonance
• Time Factors
• Tubulin (chemistry, metabolism)
• Tubulin Modulators (metabolism, pharmacology)