title: 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.affiliation: Department of Dermatology, University of Wisconsin-Madison, 1300 University Avenue, 4385 Medical Sciences Center, Madison, WI 53706, USA.
authors.forename: Eiman
authors.initials: E
authors.lastname: Mukhtar
authors.affiliation: Department of Dermatology, University of Wisconsin-Madison, 1300 University Avenue, 4385 Medical Sciences Center, Madison, WI 53706, USA.
authors.forename: Vaqar Mustafa
authors.initials: VM
authors.lastname: Adhami
authors.affiliation: Department of Chemistry and Pharmacy, University of Sassari, Via Vienna 2, 07100 Sassari, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Sechi
authors.affiliation: Department of Dermatology, University of Wisconsin-Madison, 1300 University Avenue, 4385 Medical Sciences Center, Madison, WI 53706, USA. Electronic address: hmukhtar@wisc.edu.
authors.forename: Hasan
authors.initials: H
authors.lastname: Mukhtar
mesh_terms: D000107:Acetylation; D000818:Animals; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D044948:Flavonols; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D062105:Molecular Docking Simulation; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D015398:Signal Transduction / Q000187:drug effects; D020349:Surface Plasmon Resonance; D013997:Time Factors; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism*; D050257:Tubulin Modulators / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D018797:Cell Cycle Proteins; D005419:Flavonoids; D044948:Flavonols; C489788:MAP2 protein, human; C000601103:MAP4 protein, human; D008869:Microtubule-Associated Proteins; C512648:NUDC protein, human; D009687:Nuclear Proteins; D014404:Tubulin; D050257:Tubulin Modulators; C017875:fisetin; D017239:Paclitaxel
keywords: Fisetin; Microtubules; Migration; Proliferation; Prostate cancer