title: Cancer resistance in the blind mole rat is mediated by concerted necrotic cell death mechanism.
abstract: Blind mole rats Spalax (BMR) are small subterranean rodents common in the Middle East. BMR is distinguished by its adaptations to life underground, remarkable longevity (with a maximum documented lifespan of 21 y), and resistance to cancer. Spontaneous tumors have never been observed in spalacids. To understand the mechanisms responsible for this resistance, we examined the growth of BMR fibroblasts in vitro of the species Spalax judaei and Spalax golani. BMR cells proliferated actively for 7-20 population doublings, after which the cells began secreting IFN-β, and the cultures underwent massive necrotic cell death within 3 d. The necrotic cell death phenomenon was independent of culture conditions or telomere shortening. Interestingly, this cell behavior was distinct from that observed in another long-lived and cancer-resistant African mole rat, Heterocephalus glaber, the naked mole rat in which cells display hypersensitivity to contact inhibition. Sequestration of p53 and Rb proteins using SV40 large T antigen completely rescued necrotic cell death. Our results suggest that cancer resistance of BMR is conferred by massive necrotic response to overproliferation mediated by p53 and Rb pathways, and triggered by the release of IFN-β. Thus, we have identified a unique mechanism that contributes to cancer resistance of this subterranean mammal extremely adapted to life underground.
authors.affiliation: Department of Biology, University of Rochester, Rochester, NY 14627, USA. vera.gorbunova@rochester.edu
authors.forename: Vera
authors.initials: V
authors.lastname: Gorbunova
authors.forename: Christopher
authors.initials: C
authors.lastname: Hine
authors.forename: Xiao
authors.initials: X
authors.lastname: Tian
authors.forename: Julia
authors.initials: J
authors.lastname: Ablaeva
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Gudkov
authors.forename: Eviatar
authors.initials: E
authors.lastname: Nevo
authors.forename: Andrei
authors.initials: A
authors.lastname: Seluanov
mesh_terms: D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000378:metabolism; D003260:Contact Inhibition; D060467:Disease Resistance / Q000276:immunology*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D016899:Interferon-beta / Q000378:metabolism; D008297:Male; D051379:Mice; D009336:Necrosis / Q000473:pathology*; D009369:Neoplasms / Q000473:pathology*; D010641:Phenotype; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction; D046308:Spalax / Q000276:immunology*; D059506:Telomere Shortening; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000952:Antigens, Polyomavirus Transforming; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D016899:Interferon-beta