PMID- 17005556
OWN - NLM
STAT- MEDLINE
DCOM- 20070130
LR  - 20211203
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 281
IP  - 48
DP  - 2006 Dec 1
TI  - Autophagy for cancer therapy through inhibition of pro-apoptotic proteins and 
      mammalian target of rapamycin signaling.
PG  - 36883-90
AB  - Autophagy is an alternative cell death pathway that is induced by mammalian 
      target of rapamycin (mTOR) inhibitors and up-regulated when apoptosis is 
      defective. We investigated radiation-induced autophagy in the presence or absence 
      of Bax/Bak with or without an mTOR inhibitor, Rad001. Two isogenic cell lines, 
      wild type (WT) and Bak/Bak(-/-) mouse embryonic fibroblasts and tumor cell lines 
      were used for this study. Irradiated Bak/Bak(-/-) cells had a decrease of 
      Akt/mTOR signaling and a significant increase of pro-autophagic proteins 
      ATG5-ATG12 COMPLEX and Beclin-1. These molecular events resulted in an 
      up-regulation of autophagy. Bax/Bak(-/-) cells were defective in undergoing 
      apoptosis but were more radiosensitive than the WT cells in autophagy. Both 
      autophagy and sensitization of Bak/Bax(-/-) cells were further enhanced in the 
      presence of Rad001. In contrast, inhibitors of autophagy rendered the 
      Bak/Bax(-/-) cells radioresistant, whereas overexpression of ATG5 and Beclin-1 
      made the WT cells radiosensitive. When this novel concept of radiosensitization 
      was tested in cancer models, small interfering RNAs against Bak/Bax also led to 
      increased autophagy and sensitization of human breast and lung cancer cells to 
      gamma radiation, which was further enhanced by Rad001. This is the first report 
      to demonstrate that inhibition of pro-apoptotic proteins and induction of 
      autophagy sensitizes cancer cells to therapy. Therapeutically targeting this 
      novel pathway may yield significant benefits for cancer patients.
FAU - Kim, Kwang Woon
AU  - Kim KW
AD  - Department of Radiation Oncology, Vanderbilt Ingram Cancer Center, Vanderbilt 
      University School of Medicine, Nashville, Tennessee 37232, USA.
FAU - Mutter, Robert W
AU  - Mutter RW
FAU - Cao, Carolyn
AU  - Cao C
FAU - Albert, Jeffrey M
AU  - Albert JM
FAU - Freeman, Michael
AU  - Freeman M
FAU - Hallahan, Dennis E
AU  - Hallahan DE
FAU - Lu, Bo
AU  - Lu B
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20060927
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (bcl-2 Homologous Antagonist-Killer Protein)
RN  - 0 (bcl-2-Associated X Protein)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - *Apoptosis
MH  - *Autophagy
MH  - Cell Line, Tumor
MH  - Dose-Response Relationship, Radiation
MH  - Everolimus
MH  - Humans
MH  - Immunosuppressive Agents/pharmacology
MH  - Mice
MH  - Mice, Knockout
MH  - Neoplasms/*therapy
MH  - Protein Kinases/metabolism/*physiology
MH  - Signal Transduction
MH  - Sirolimus/analogs & derivatives/pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - bcl-2 Homologous Antagonist-Killer Protein/genetics/physiology
MH  - bcl-2-Associated X Protein/genetics/physiology
EDAT- 2006/09/29 09:00
MHDA- 2007/01/31 09:00
CRDT- 2006/09/29 09:00
PHST- 2006/09/29 09:00 [pubmed]
PHST- 2007/01/31 09:00 [medline]
PHST- 2006/09/29 09:00 [entrez]
AID - S0021-9258(20)72035-1 [pii]
AID - 10.1074/jbc.M607094200 [doi]
PST - ppublish
SO  - J Biol Chem. 2006 Dec 1;281(48):36883-90. doi: 10.1074/jbc.M607094200. Epub 2006 
      Sep 27.