title: Radiation-Induced Loss of Salivary Gland Function Is Driven by Cellular Senescence and Prevented by IL6 Modulation.
abstract: Head and neck cancer patients treated by radiation commonly suffer from a devastating side effect known as dry-mouth syndrome, which results from the irreversible loss of salivary gland function via mechanisms that are not completely understood. In this study, we used a mouse model of radiation-induced salivary hypofunction to investigate the outcomes of DNA damage in the head and neck region. We demonstrate that the loss of salivary function was closely accompanied by cellular senescence, as evidenced by a persistent DNA damage response (γH2AX and 53BP1) and the expression of senescence-associated markers (SA-βgal, p19ARF, and DcR2) and secretory phenotype (SASP) factors (PAI-1 and IL6). Notably, profound apoptosis or necrosis was not observed in irradiated regions. Signs of cellular senescence were also apparent in irradiated salivary glands surgically resected from human patients who underwent radiotherapy. Importantly, using IL6 knockout mice, we found that sustained expression of IL6 in the salivary gland long after initiation of radiation-induced DNA damage was required for both senescence and hypofunction. Additionally, we demonstrate that IL6 pretreatment prevented both senescence and salivary gland hypofunction via a mechanism involving enhanced DNA damage repair. Collectively, these results indicate that cellular senescence is a fundamental mechanism driving radiation-induced damage in the salivary gland and suggest that IL6 pretreatment may represent a promising therapeutic strategy to preserve salivary gland function in head and neck cancer patients undergoing radiotherapy.
authors.affiliation: Goldyne-Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: Yitzhak
authors.initials: Y
authors.lastname: Marmary
authors.affiliation: Goldyne-Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: Revital
authors.initials: R
authors.lastname: Adar
authors.affiliation: Goldyne-Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Gaska
authors.affiliation: Department of Oncology, Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: Annette
authors.initials: A
authors.lastname: Wygoda
authors.affiliation: Department of Pathology, Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: Alexander
authors.initials: A
authors.lastname: Maly
authors.affiliation: Department of Otolaryngology/Head and Neck Surgery, Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cohen
authors.affiliation: Department of Otolaryngology/Head and Neck Surgery, Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: Ron
authors.initials: R
authors.lastname: Eliashar
authors.affiliation: Goldyne-Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: Lina
authors.initials: L
authors.lastname: Mizrachi
authors.affiliation: Goldyne-Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: Carmit
authors.initials: C
authors.lastname: Orfaig-Geva
authors.affiliation: Molecular Physiology and Therapeutics Branch National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland.
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Baum
authors.affiliation: Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.affiliation: Goldyne-Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: Eithan
authors.initials: E
authors.lastname: Galun
authors.affiliation: Goldyne-Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel. axelrod@hadassah.org.il.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Axelrod
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D016922:Cellular Senescence; D004249:DNA Damage; D004260:DNA Repair; D005260:Female; D006258:Head and Neck Neoplasms / Q000532:radiotherapy*; D006657:Histones / Q000032:analysis; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D019947:Receptors, Interleukin-6 / Q000502:physiology; D012469:Salivary Glands / Q000502:physiology / Q000528:radiation effects*
chemical_list: D006657:Histones; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; C475961:gamma-H2AX protein, mouse