Increased susceptibility of breast cancer cells to stress mediated inhibition of protein synthesis

Authors:
Pervin S, Tran AH, Zekavati S, Fukuto JM, Singh R, Chaudhuri G
In:
Source: Cancer Res
Publication Date: (2008)
Issue: 68(12): 4862-74
Research Area:
Cancer Research/Cell Biology
Cells used in publication:
MDA-MB-231
Species: human
Tissue Origin: breast
Platform:
Nucleofectorâ„¢ I/II/2b
Abstract
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.