Autophagy exacerbates caspase-dependent apoptotic cell death after short times of starvation.
Biochem Pharmacol
; 98(4): 573-86, 2015 Dec 15.
Article
em En
| MEDLINE
| ID: mdl-26441250
ABSTRACT
Autophagy is generally regarded as a mechanism to promote cell survival. However, autophagy can occasionally be the mechanism responsible of cell demise. We have found that a concomitant depletion of glucose, nutrients and growth factors provoked cell death in a variety of cell lines. This death process was contingent upon caspase activation and was mediated by BAX/BAK proteins, thus indicating its apoptotic nature and the engagement of an intrinsic pathway. In order to abrogate autophagy, 3-methyladenine (3-MA), BECLIN-1 siRNA and Atg5 knock-out (Tet-Off type) approaches were alternatively employed. Irrespective of the procedure, at short times of starvation, we found that the ongoing autophagy was sensitizing cells to the permeabilization of the mitochondrial outer membrane (MOMP), caspase activation and, therefore, apoptosis. On the contrary, at longer times of starvation, autophagy displayed its characteristic pro-survival effect on cells. As far as we know, we provide the first experimental paradigm where time is the only variable determining the final outcome of autophagy. In other words, we have circumscribed in time the shift transforming autophagy from a cell death to a protection mechanism. Moreover, at short times, starvation-driven autophagy exacerbated the apoptotic cell death caused by several antitumor agents. In agreement with this fact, their apoptotic effects were greatly diminished by autophagy inhibition. The implications of these facts in tumor biology will be discussed.
Palavras-chave
2-Phenylethynesulfonamide (Pubmed CID 327653); 3-Methyladenine (Pubmed CID 1673); 7-Bromoindirubin-3-oxime (Pubmed CID 11846148); Apoptosis; Autophagy; Camptothecin (Pubmed CID 24360); Caspases; Etoposide (Pubmed CID 36462); Mitochondrial permeabilization; Necrostatin-1 (Pubmed CID 282833); Q-VD-OPh (Pubmed CID 11237609); Short-term starvation; Staurosporine (Pubmed CID 44259)
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Autofagia
/
Apoptose
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Caspases
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article