PMID- 16322256
OWN - NLM
STAT- MEDLINE
DCOM- 20060125
LR  - 20221109
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 65
IP  - 23
DP  - 2005 Dec 1
TI  - Rapamycin-sensitive pathway regulates mitochondrial membrane potential, 
      autophagy, and survival in irradiated MCF-7 cells.
PG  - 11061-70
AB  - Radiation-induced inhibition of rapamycin-sensitive pathway and its effect on the 
      cellular response to radiation were studied in the human breast cancer cell line 
      MCF-7. Both radiation and rapamycin shared molecular targets and induced similar 
      physiologic responses. Each of these treatments increased immunostaining of 
      mammalian target of rapamycin (mTOR) in the nucleus, and radiation led to 
      decreased phosphorylation of its autophosphorylation site Ser2481. In addition to 
      dephosphorylation of established mTOR downstream effectors 4E-binding protein 1 
      and p70 ribosomal S6 kinase, both treatments decreased the level of eukaryotic 
      initiation factor 4G. Experiments with the potentiometric dye, JC-1, revealed an 
      oligomycin-dependent increase in mitochondrial membrane potential following 
      radiation or rapamycin treatment, suggesting that both lead to reversal of 
      F0F1ATPase activity. Both radiation and rapamycin induced sequestration of 
      cytoplasmic material in autophagic vacuoles. In both cases, appearance of 
      autophagic vacuoles involved the participation of microtubule-associated protein 
      1 light chain 3 (LC3). Transient cotransfection of green fluorescent protein-LC3 
      with either wild-type or dominant-negative mTOR further showed that inactivation 
      of mTOR pathway is sufficient to induce autophagy in these cells. Finally, 
      administration of rapamycin in combination with radiation led to enhanced 
      mitochondria hyperpolarization, p53 phosphorylation, and increased cell death. 
      Taken together, these experiments show that radiation-induced inhibition of 
      rapamycin-sensitive pathway in MCF-7 cells causes changes in mitochondria 
      metabolism, development of autophagy, and an overall decrease in cell survival.
FAU - Paglin, Shoshana
AU  - Paglin S
AD  - Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New 
      York, New York 10021, USA. paglins@mskcc.org
FAU - Lee, Na-Young
AU  - Lee NY
FAU - Nakar, Charles
AU  - Nakar C
FAU - Fitzgerald, Megan
AU  - Fitzgerald M
FAU - Plotkin, Jason
AU  - Plotkin J
FAU - Deuel, Bethanne
AU  - Deuel B
FAU - Hackett, Nadia
AU  - Hackett N
FAU - McMahill, Melissa
AU  - McMahill M
FAU - Sphicas, Eleana
AU  - Sphicas E
FAU - Lampen, Nina
AU  - Lampen N
FAU - Yahalom, Joachim
AU  - Yahalom J
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (TP53 protein, human)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - 0 (protein kinase modulator)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adenocarcinoma/drug therapy/metabolism/pathology/radiotherapy
MH  - Antibiotics, Antineoplastic/antagonists & inhibitors/pharmacology
MH  - Autophagy/drug effects/physiology/*radiation effects
MH  - Breast Neoplasms/drug therapy/metabolism/pathology/*radiotherapy
MH  - Cell Line, Tumor
MH  - Cell Survival/drug effects/physiology/radiation effects
MH  - Cytoplasm/enzymology/metabolism
MH  - Humans
MH  - Intracellular Membranes/drug effects/physiology/radiation effects
MH  - Intracellular Signaling Peptides and Proteins/pharmacology
MH  - Membrane Potentials/drug effects/physiology/radiation effects
MH  - Mitochondria/drug effects/physiology/*radiation effects
MH  - Phosphorylation/radiation effects
MH  - Protein Kinases/*metabolism
MH  - Sirolimus/antagonists & inhibitors/*pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Tumor Suppressor Protein p53/metabolism
MH  - Vacuoles/enzymology/metabolism
EDAT- 2005/12/03 09:00
MHDA- 2006/01/26 09:00
CRDT- 2005/12/03 09:00
PHST- 2005/12/03 09:00 [pubmed]
PHST- 2006/01/26 09:00 [medline]
PHST- 2005/12/03 09:00 [entrez]
AID - 65/23/11061 [pii]
AID - 10.1158/0008-5472.CAN-05-1083 [doi]
PST - ppublish
SO  - Cancer Res. 2005 Dec 1;65(23):11061-70. doi: 10.1158/0008-5472.CAN-05-1083.