AMPK-mediated autophagy inhibits apoptosis in cisplatin-treated tumour cells
2009
Autori:
Harhaji-Trajković, LjubicaVilimanovich, Urosh
Kravić-Stevović, Tamara
Bumbaširević, Vladimir
Trajković, Vladimir
Tip dokumenta:
Članak u časopisu (Objavljena verzija)
,
© 2009 The Authors Journal compilation © 2009 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd
Metapodaci
Prikaz svih podataka o dokumentuApstrakt:
The role of autophagy in cisplatin anticancer action was investigated using human U251 glioma, rat C6 glioma and mouse L929 fibrosarcoma cell lines. A dose- and time-dependent induction of autophagy was observed in tumour cells following cisplatin treatment, as demonstrated by up-regulation of autophagy-inducing protein beclin-1 and subsequent appearance of acridine orange-stained acidic autophagic vesicles. The presence of autophagosomes in cisplatin-treated cells was also confirmed by electron microscopy. Inhibition of autophagy with lysosomal inhibitors bafilomycin A1 and chloroquine, or a PI3 kinase inhibitor wortmannin, markedly augmented cisplatin-triggered oxidative stress and caspase activation, leading to an increase in DNA fragmentation and apoptotic cell death. The mechanisms underlying the protective effect of autophagy apparently involved the interference with cisplatin-induced modulation of Bcl-2 family proteins, as inhibition of autophagy potentiated cisplatin-mediated up-regulation of proapoptotic Bax and down-regulation of anti-apoptotic Bcl-2. Autophagy induction in cisplatin-treated cells was preceded by activation of adenosine monophosphate-activated protein kinase (AMPK) and concomitant down-regulation of mammalian target of rapamycin (mTOR)-mediated phosphorylation of p70S6 kinase. The ability of cisplatin to trigger autophagy was reduced by small interfering RNA (siRNA)-mediated AMPK silencing, while transfection with mTOR siRNA was sufficient to trigger autophagy in tumour cells. Finally, siRNA-mediated AMPK down-regulation and AMPK inhibitor compound C increased cisplatin-induced tumour cell death, while mTOR siRNA and AMPK activator metformin protected tumour cells from cisplatin. Taken together, these data suggest that cisplatin-triggered activation of AMPK and subsequent suppression of mTOR activity can induce an autophagic response that protects tumour cells from cisplatin-mediated apoptotic death.
Ključne reči:
cisplatin; cancer; autophagy; apoptosis; AMPK; mTORIzvor:
Journal of Cellular and Molecular Medicine, 2009, 13, 9B, 3644-3654Finansiranje / projekti:
- Citotoksični, citoprotektivni i imunomodulatorni efekti nanočestica (RS-MESTD-MPN2006-2010-145073)
- Molekularni mehanizmi regulacije ćelijske smrti u fiziološkim i patološkim uslovima (RS-MESTD-MPN2006-2010-145058)
- Fiziološka i farmakološka modulacija imunoinflamatornih i malignih bolesti (RS-MESTD-MPN2006-2010-143029)
DOI: 10.1111/j.1582-4934.2009.00663.x
ISSN: 1582-4934
PubMed: 20196784