期刊
CANCER RESEARCH
卷 68, 期 12, 页码 4862-4874出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-08-0074
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- NCI NIH HHS [CA-78357, R01 CA078357-05, R01 CA078357] Funding Source: Medline
- NCRR NIH HHS [G12-RR03026] Funding Source: Medline
- NIA NIH HHS [SC1 AG033407] Funding Source: Medline
- NICHD NIH HHS [R03 HD053888, R03 HD053888-01A1, 1R03 HD053888-01A1] Funding Source: Medline
- NIGMS NIH HHS [S06 GM068510, S06 GM068510-010003, 1S06-GM068510-03] Funding Source: Medline
Protein synthesis is a tightly controlled process, and its deregulation plays an important role in tumorigenesis. Protein synthesis remains poorly understood with very few well-identified validated targets for therapeutic purposes. In this study, we use nitric oxide (NO), which suppresses protein synthesis by inactivating eukaryotic initiation factor 2-alpha (eIF2-alpha), to examine the mechanism by which low and high oxidative stress inhibits protein synthesis. In breast cancer cells, low NO stress induced heme-regulated inhibitor (HRI) activation, which facilitated gradual decline in short half-life proteins. High NO stress induced HRI and protein kinase R (PKR) activation, leading to a sharp decline in protein synthesis as accessed by a decline in short and long half-life proteins and dramatic morphologic changes. In contrast, human mammary epithelial (HME) and Ras transfected untransformed HME (MCF-10A1 neo N) cells were less susceptible to NO-induced inhibition of protein synthesis and cytostasis. Our results suggest that NO-induced cytostasis in breast cancer cells was due to PKR activation and increased phosphorylation of eIF2-alpha, whereas the reduced susceptibility of normal mammary epithelial cells to NO could be due to the inaccessibility of PKR, which is bound to inhibitor p58.
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