Tau dephosphorylation and microfilaments disruption are upstream events of the anti-proliferative effects of DADS in SH-SY5Y cells.
Garlic organosulphur compounds have been successfully used as redox anti-proliferative agents. In this work, we dissect the effects of diallyl disulphide (DADS) focusing on the events upstream of cell cycle arrest and apoptosis induced in neuroblastoma SH-SY5Y cells. We demonstrate that DADS is able to cause early morphological changes, cytoskeleton oxidation, microfilaments reduction and depolymerization of microtubules. These events are attenuated in cells stably overexpressing the antioxidant enzyme SOD1, suggesting that superoxide plays a crucial role in destabilizing cytoskeleton. Moreover, we evidence that the main microtubules-associated protein Tau undergoes PP1-mediated dephosphorylation as demonstrated by treatment with okadaic acid as well as by immunoreaction with anti-Tau-1 antibody, which specifically recognizes its dephosphorylated forms. Tau dephosphorylation is inhibited by the two-electron reductants NAC and GSH ester but not by SOD1. The inability of DADS to induce apoptosis in neuroblastoma-differentiated cells gives emphasis to the anti-proliferative activity of DADS, which can be regarded as a promising potent anti-neuroblastoma drug by virtue of its widespread cytoskeleton disrupting action on proliferating cells.
Aquilano
Katia
K
Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, 00133, Rome, Italy.
Vigilanza
Paola
P
Filomeni
Giuseppe
G
Rotilio
Giuseppe
G
Ciriolo
Maria R
MR
D008841:Actin Cytoskeleton / Q000378:metabolism*; D000498:Allyl Compounds / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D004220:Disulfides / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D008856:Microscopy, Fluorescence; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D013481:Superoxides / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
D000498:Allyl Compounds; D004220:Disulfides; D017382:Reactive Oxygen Species; C000606290:SOD1 protein, human; D016875:tau Proteins; D013481:Superoxides; C028009:diallyl disulfide; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1