Study of the pathways involved in apoptosis induced by PI3K inhibition in cerebellar granule neurons

Vazquez de la Torre, Aurelio; Junyent, Felix; Folch, Jaume; Pelegri, Carme; Vilaplana, Jordi; Auladell, Carme; Beas-Zarate, Carlos; Pallas, Merce; Camins, Antoni; Verdaguer, Ester


In the present study we focused in the PI3K/Akt pathway which plays a key role in neuronal survival. Here we show that inhibition of PI3K/Akt by means of LY294002 induces apoptosis via a caspase-dependent and calpain-independent pathway in cerebellar granule neurons (CGNs). This finding was confirmed using zVAD-fmk, a widely caspase inhibitor that prevents apoptosis. For this purpose, we compared two models of apoptosis in CGNs, namely inhibition of PI3K/Akt, and serum potassium deprivation (S/K deprivation). In contrast to the S/K deprivation model, caspase-3 was not activated when PI3K is inhibited. Likewise, CDK5 activation was not involved in this apoptotic process, because calpain activation is responsible for the formation of CDK5/p25 neurotoxic form. However, S/K deprivation activated calpain, as it is shown by alpha-spectrin breakdown, and favoured the formation of CDK5/p25. Moreover, although PI3K/Akt inhibition enhanced pRbser780 phosphorylation, no increase in the expression of cell-cycle proteins, namely: cyclin D, cyclin E. CDK2 or CDK4, was detected. Furthermore, BrdU incorporation assay did not shown any increase in DNA synthesis. Likewise, PI3K/Akt inhibition increased GSK3 beta activity and c-Jun phosphorylation, which implicates these two pathways in this apoptotic route. Although previous reports suggest that apoptosis induced in CGNs by LY294002 and S/K deprivation causes PI3K inhibition and increases GSK3 beta activity and c-Jun phosphorylation activation, our results demonstrate substantial differences between them and point to a key role of GSK3 beta in the apoptosis induced in CGNs in the two models tested. (C) 2011 Elsevier B.V. All rights reserved.

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Título según WOS: ID WOS:000294091600009 Not found in local WOS DB
Volumen: 59
Número: 2
Fecha de publicación: 2011
Página de inicio: 159
Página final: 167


Notas: ISI