Department of Biochemistry and Molecular Biology, University of Southern California Keck School of Medicine, USC Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, Los Angeles, CA 90089-9176, United States.
Longevity Institute, Leonard Davis School of Gerontology and Department of Biological Sciences, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191, United States.
Sci Rep. 2017 Feb 1;7:40919. doi: 10.1038/srep40919.
GRP78, a multifunctional protein with potent cytoprotective properties, is an emerging therapeutic target to combat cancer development, progression and drug resistance. The biological consequences of prolonged reduction in expression of this essential chaperone which so far has been studied primarily in young mice, was investigated in older mice, as older individuals are likely to be important recipients of anti-GRP78 therapy. We followed cohorts of Grp78 and Grp78 male and female mice up to 2 years of age in three different genetic backgrounds and characterized them with respect to body weight, organ integrity, behavioral and memory performance, cancer, inflammation and chemotoxic response. Our results reveal that body weight, organ development and integrity were not impaired in aged Grp78 mice. No significant effect on cancer incidence and inflammation was observed in aging mice. Interestingly, our studies detected some subtle differential trends between the WT and Grp78 mice in some test parameters dependent on gender and genetic background. Our studies provide the first evidence that GRP78 haploinsufficiency for up to 2 years of age has no major deleterious effect in rodents of different genetic background, supporting the merit of anti-GRP78 drugs in treatment of cancer and other diseases affecting the elderly.
GRP78 是一种具有强大细胞保护特性的多功能蛋白，是一种新兴的治疗靶点，可用于对抗癌症的发生、发展和耐药性。目前，这种必需伴侣蛋白的表达长期减少主要在年轻小鼠中进行了研究，本研究探讨了在老年小鼠中这种表达长期减少的生物学后果，因为老年个体可能是抗 GRP78 治疗的重要接受者。我们在三种不同的遗传背景下对 Grp78 和 Grp78 雄性和雌性小鼠进行了跟踪研究，直到它们 2 岁，并对它们的体重、器官完整性、行为和记忆表现、癌症、炎症和化学毒性反应进行了特征描述。研究结果表明，老年 Grp78 小鼠的体重、器官发育和完整性没有受损。在衰老小鼠中，没有观察到癌症发病率和炎症的显著影响。有趣的是，我们的研究在一些依赖于性别和遗传背景的测试参数中检测到 WT 和 Grp78 小鼠之间存在一些微妙的差异趋势。本研究首次提供证据表明，GRP78 杂合不足长达 2 年对不同遗传背景的啮齿动物没有重大的有害影响，支持了抗 GRP78 药物在治疗癌症和其他影响老年人疾病方面的价值。
