title: Key role of phosphodiesterase 4A (PDE4A) in autophagy triggered by yessotoxin.
abstract: Understanding the mechanism of action of the yessotoxin (YTX) is crucial since this drug has potential pharmacological effects in allergic processes, tumor proliferation and neurodegenerative diseases. It has been described that YTX activates apoptosis after 24h of treatment, while after 48 h of incubation with the toxin a decrease in cell viability corresponding to cellular differentiation or non-apoptotic cell death was observed. In this paper, these processes were extensively studied by using the erythroleukemia K-562 cell line. On one hand, events of K-562 cell differentiation into erythrocytes after YTX treatment were studied using hemin as positive control of cell differentiation. Cell differentiation was studied through the cyclic nucleotide response element binding (phospho-CREB) and the transferrin receptor (TfR) expression. On the other hand, using rapamycin as positive control, autophagic hallmarks, as non-apoptotic cell death, were studied after toxin exposure. In this case, the mechanistic target of rapamycin (mTOR) and light chain 3B (LC3B) levels were measured to check autophagy activation. The results showed that cell differentiation was not occurring after 48 h of toxin incubation while at this time the autophagy was triggered. Furthermore after 24h of toxin treatment none of these processes were activated. In addition, the role of the type 4A phosphodiesterase (PDE4A), the intracellular target of YTX, was checked. PDE4A-silencing experiments showed different regulation steps of PDE4A in the autophagic processes triggered either by traditional compounds or YTX. In summary, after 48 h YTX treatment PDE4A-dependent autophagy, as non-apoptotic programmed cell death, is activated.
authors.affiliation: Dept. Farmacología, Facultad de Veterinaria, 27002 Lugo, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Fernández-Araujo
authors.affiliation: Dept. Farmacología, Facultad de Veterinaria, 27002 Lugo, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Alfonso
authors.affiliation: Dept. Fisiología, Facultad de Veterinaria, 27002 Lugo, Spain.
authors.forename: M R
authors.initials: MR
authors.lastname: Vieytes
authors.affiliation: Dept. Farmacología, Facultad de Veterinaria, 27002 Lugo, Spain. Electronic address: Luis.Botana@usc.es.
authors.forename: L M
authors.initials: LM
authors.lastname: Botana
mesh_terms: D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000235:genetics / Q000378:metabolism*; D020868:Gene Silencing; D006801:Humans; D020014:K562 Cells; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008978:Mollusk Venoms; D035964:Oxocins / Q000633:toxicity*; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C068126:CD71 antigen; C502070:MAP1LC3B protein, human; D008869:Microtubule-Associated Proteins; D008978:Mollusk Venoms; D035964:Oxocins; D011990:Receptors, Transferrin; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517355:PDE4A protein, human; C066632:yessotoxin; D020123:Sirolimus
keywords: Autophagy; LC3; TfR; YTX; mTOR