title: ROS-independent JNK activation and multisite phosphorylation of Bcl-2 link diallyl tetrasulfide-induced mitotic arrest to apoptosis.
abstract: Garlic-derived organosulfur compounds including diallyl polysulfides are well known for various health-beneficial properties and recent reports even point to a potential role of diallyl polysulfides as chemopreventive and therapeutic agents in cancer treatment due to their selective antiproliferative effects. In this respect, diallyl tri- and tetrasulfide are reported as strong inducers of an early mitotic arrest and subsequent apoptosis, but the underlying molecular mechanisms and the link between these two events are not yet fully elucidated. Our data revealed that diallyl tetrasulfide acts independently of reactive oxygen species and tubulin represents one of its major cellular targets. Tubulin depolymerization prevents the formation of normal spindle microtubules, thereby leading to G2/M arrest. Here, we provide evidence that c-jun N-terminal kinase, which is activated early in response to diallyl tetrasulfide treatment, mediates multisite phosphorylation and subsequent proteolysis of the anti-apoptotic protein B-cell lymphoma 2. As the latter event occurs concomitantly with the onset of apoptosis and the chemical c-jun N-terminal kinase inhibitor SP600125 not only prevented B-cell lymphoma 2 phosphorylation and proteolysis but also apoptosis following diallyl tetrasulfide treatment, we suggest that these c-jun N-terminal kinase-mediated modulations of B-cell lymphoma 2 represent the missing link connecting early microtubule inactivation to the induction of apoptosis.
authors: Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Fondation de Recherche Cancer et Sang, Hôpital Kirchberg, 9, rue Edward Steichen, L-2540 Luxembourg, Luxembourg, Germany.
authors: Mareike
authors: M
authors: Kelkel
authors: Claudia
authors: C
authors: Cerella
authors: Fabienne
authors: F
authors: Mack
authors: Thomas
authors: T
authors: Schneider
authors: Claus
authors: C
authors: Jacob
authors: Marc
authors: M
authors: Schumacher
authors: Mario
authors: M
authors: Dicato
authors: Marc
authors: M
authors: Diederich
mesh_terms: D000498:Allyl Compounds / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000378:metabolism / Q000473:pathology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008938:Mitosis / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013440:Sulfides / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000498:Allyl Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D013440:Sulfides; D014404:Tubulin; D048670:MAP Kinase Kinase 4; D020169:Caspases; C431585:diallyl tetrasulfide