Activation of the integrated stress response regulates lovastatin-induced apoptosis.

Activation of the integrated stress response regulates lovastatin-induced apoptosis. Research Abstract Details 

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Activation of the integrated stress response regulates lovastatin-induced apoptosis. Abstract Text:

Nima Niknejad,Melissa Morley,Jim Dimitroulakos,Nima Niknejad,Melissa Morley,Jim Dimitroulakos,

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.

Activation of the integrated stress response regulates lovastatin-induced apoptosis. Publishing Authors By Initials

N Niknejad,M Morley,J Dimitroulakos,N Niknejad,M Morley,J Dimitroulakos,

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Activation of the integrated stress response regulates lovastatin-induced apoptosis. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: The Journal of biological chemistry

VOLUME: 282

Page Numbers: 29748-56

Journal Abbreviation: J. Biol. Chem.

ISSN: 0021-9258

DAY: 14

MONTH: 08

YEAR: 2007

Activation of the integrated stress response regulates lovastatin-induced apoptosis. Information

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LANGUAGE: eng

NlmUniqueID: 2985121

Activation of the integrated stress response regulates lovastatin-induced apoptosis. Keywords Mesh Terms:

KEYWORDS: Prodrugs

MESH TERMS: chemistry

Chemical & Substance for Abstract: Activation of the integrated stress response regulates lovastatin-induced apoptosis. Information

Substance Name: Lovastatin

Registry Number: 75330-75-5

Grant and Affiliation Information for Activation of the integrated stress response regulates lovastatin-induced apoptosis.

AFFILIATION: Centre for Cancer Therapeutics, Ottawa Health Research Institute, Ontario K1H 8L6, Canada.

Country: United States

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MEDLINETA: J Biol Chem

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