title: Effects of Prolonged GRP78 Haploinsufficiency on Organ Homeostasis, Behavior, Cancer and Chemotoxic Resistance in Aged Mice.
abstract: 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.
authors.affiliation: 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.
authors.forename: Amy S
authors.initials: AS
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brandhorst
authors.affiliation: 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.
authors.forename: Daisy F
authors.initials: DF
authors.lastname: Rangel
authors.affiliation: 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.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Navarrete
authors.affiliation: 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.
authors.forename: Pinchas
authors.initials: P
authors.lastname: Cohen
authors.affiliation: 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.
authors.forename: Valter D
authors.initials: VD
authors.lastname: Longo
authors.affiliation: Zilkha Neurogenetic Institute, Department of Cell and Neurobiology &Department of Ophthalmology, University of Southern California Keck School of Medicine, 1501 San Pablo Street, Los Angeles, CA 90033, United States.
authors.forename: Jeannie
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Preventive Medicine, University of Southern California Keck School of Medicine, 1441 Eastlake Avenue, Los Angeles, CA 90033, United States.
authors.forename: Susan
authors.initials: S
authors.lastname: Groshen
authors.affiliation: 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.
authors.forename: Todd E
authors.initials: TE
authors.lastname: Morgan
authors.affiliation: Department of Pathology, University of Southern California Keck School of Medicine, USC Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, Los Angeles, CA 90089-9176, United States.
authors.forename: Louis
authors.initials: L
authors.lastname: Dubeau
mesh_terms: D000375:Aging / Q000235:genetics* / Q000473:pathology / Q000502:physiology; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001522:Behavior, Animal; D001835:Body Weight; D064419:Chemically-Induced Disorders / Q000235:genetics; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D057895:Haploinsufficiency; D006360:Heat-Shock Proteins / Q000235:genetics*; D006706:Homeostasis; D008297:Male; D008568:Memory; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse