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Increased Susceptibility of Breast Cancer Cells to Stress Mediated Inhibition of Protein Synthesis

¹ Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California, Los Angeles; ² Department of Molecular and Medical Pharmacology; ³ Division of Endocrinology and RCMI Molecular Medicine Core Laboratory at Charles Drew University of Medicine and Science; and ⁴ Jonsson Comprehensive Cancer Center, Los Angeles, California

Requests for reprints: Shehla Pervin, Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California, Los Angeles, 13-952 Factor Building, 650 Charles Young Drive, South, Los Angeles, CA 90095. Phone: 310-794-5793; Fax: 310-206-5991; E-mail: spervin{at}mednet.ucla.edu.

Key Words: NO • translation • PKR • cyclin D1 • eIF2-

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- (eIF2-), 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-, 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. [Cancer Res 2008;68(12):4862–74]