PMID- 17699156
OWN - NLM
STAT- MEDLINE
DCOM- 20071127
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 282
IP  - 41
DP  - 2007 Oct 12
TI  - Activation of the integrated stress response regulates lovastatin-induced 
      apoptosis.
PG  - 29748-56
AB  - Lovastatin, a potent inhibitor of mevalonate synthesis, can readily induce 
      apoptosis in a subset of human tumor types including head and neck squamous cell 
      carcinomas (HNSCC). We recently identified activation of transcription factor 
      (ATF) 4 as a lovastatin induced gene in HNSCC cells. ATF4 plays a significant 
      role in regulating cellular responses to a wide variety of stress inducers known 
      as the integrated stress response (ISR). These cell stresses lead to the 
      phosphorylation of eukaryotic initiation factor (eIF) 2alpha shutting down global 
      protein translation. However, the translation of ATF4 is enhanced. In this study, 
      lovastatin treatment induced eIF2alpha phosphorylation and inhibited global 
      protein translation. ATF4 expression was induced followed by increased ATF3 and 
      CHOP expression, targets of ATF4 activity, in SCC25 HNSCC cells. In CHOP(-/-) 
      murine embryonic fibroblasts (MEFs), lovastatin-induced apoptosis was attenuated 
      indicating a role for CHOP in this response. Furthermore, the eIF2alpha kinase 
      GCN2 mediates lovastatin induction of ATF4 and lovastatin-induced apoptosis was 
      also attenuated in GCN2(-/-) MEFs. The pro-drug version of lovastatin has 
      potential proteasome inhibitory activity and recently a variety of well 
      established proteasome inhibitors were shown to activate the ISR. In this study, 
      neither the pro-drug nor the active forms of lovastatin had any significant 
      effect on proteasome activity. Therefore, lovastatin, by targeting mevalonate 
      synthesis, is a potent inducer of the ISR through a novel and as yet unrecognized 
      mechanism.
FAU - Niknejad, Nima
AU  - Niknejad N
AD  - Centre for Cancer Therapeutics, Ottawa Health Research Institute, Ontario K1H 
      8L6, Canada.
FAU - Morley, Melissa
AU  - Morley M
FAU - Dimitroulakos, Jim
AU  - Dimitroulakos J
LA  - eng
PT  - Journal Article
DEP - 20070814
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Eukaryotic Initiation Factor-2)
RN  - 0 (Prodrugs)
RN  - 9LHU78OQFD (Lovastatin)
RN  - S5UOB36OCZ (Mevalonic Acid)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*therapeutic use
MH  - *Apoptosis
MH  - Carcinoma, Squamous Cell/*drug therapy
MH  - Cell Line, Tumor
MH  - Drug Screening Assays, Antitumor
MH  - Eukaryotic Initiation Factor-2/metabolism
MH  - Fibroblasts/metabolism
MH  - Head and Neck Neoplasms/*drug therapy
MH  - Humans
MH  - Lovastatin/*therapeutic use
MH  - Mevalonic Acid/metabolism
MH  - Mice
MH  - Models, Biological
MH  - Phosphorylation
MH  - Prodrugs/chemistry
EDAT- 2007/08/19 09:00
MHDA- 2007/12/06 09:00
CRDT- 2007/08/19 09:00
PHST- 2007/08/19 09:00 [pubmed]
PHST- 2007/12/06 09:00 [medline]
PHST- 2007/08/19 09:00 [entrez]
AID - S0021-9258(20)71732-1 [pii]
AID - 10.1074/jbc.M705859200 [doi]
PST - ppublish
SO  - J Biol Chem. 2007 Oct 12;282(41):29748-56. doi: 10.1074/jbc.M705859200. Epub 2007 
      Aug 14.