PMID- 20196784
OWN - NLM
STAT- MEDLINE
DCOM- 20111223
LR  - 20211203
IS  - 1582-4934 (Electronic)
IS  - 1582-1838 (Print)
IS  - 1582-1838 (Linking)
VI  - 13
IP  - 9B
DP  - 2009 Sep
TI  - AMPK-mediated autophagy inhibits apoptosis in cisplatin-treated tumour cells.
PG  - 3644-54
LID - 10.1111/j.1582-4934.2009.00663.x [doi]
AB  - 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.
FAU - Harhaji-Trajkovic, L
AU  - Harhaji-Trajkovic L
AD  - Institute for Biological Research, Belgrade, Serbia. vtrajkovic@eunet.rs
FAU - Vilimanovich, U
AU  - Vilimanovich U
FAU - Kravic-Stevovic, T
AU  - Kravic-Stevovic T
FAU - Bumbasirevic, V
AU  - Bumbasirevic V
FAU - Trajkovic, V
AU  - Trajkovic V
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - J Cell Mol Med
JT  - Journal of cellular and molecular medicine
JID - 101083777
RN  - 0 (Antineoplastic Agents)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - Q20Q21Q62J (Cisplatin)
SB  - IM
MH  - AMP-Activated Protein Kinases/*metabolism
MH  - Animals
MH  - Antineoplastic Agents/pharmacology
MH  - *Apoptosis
MH  - Autophagy
MH  - Cell Line, Tumor
MH  - Cisplatin/*pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Gene Silencing
MH  - Humans
MH  - Mice
MH  - Microscopy, Electron, Transmission/methods
MH  - Neoplasms/*drug therapy/*metabolism
MH  - Rats
MH  - TOR Serine-Threonine Kinases/metabolism
PMC - PMC4516513
EDAT- 2010/03/04 06:00
MHDA- 2011/12/24 06:00
PMCR- 2009/09/01
CRDT- 2010/03/04 06:00
PHST- 2010/03/04 06:00 [entrez]
PHST- 2010/03/04 06:00 [pubmed]
PHST- 2011/12/24 06:00 [medline]
PHST- 2009/09/01 00:00 [pmc-release]
AID - JCMM663 [pii]
AID - 10.1111/j.1582-4934.2009.00663.x [doi]
PST - ppublish
SO  - J Cell Mol Med. 2009 Sep;13(9B):3644-54. doi: 10.1111/j.1582-4934.2009.00663.x.