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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. 

Author information

Marmary Y1, Adar R1, Gaska S1, Wygoda A2, Maly A3, Cohen J4, Eliashar R4, Mizrachi L1, Orfaig-Geva C1, Baum BJ5, Rose-John S6, Galun E1, Axelrod JH7.​

1Goldyne-Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.

2Department of Oncology, Hadassah Hebrew University Hospital, Jerusalem, Israel.

3Department of Pathology, Hadassah Hebrew University Hospital, Jerusalem, Israel.

4Department of Otolaryngology/Head and Neck Surgery, Hadassah Hebrew University Hospital, Jerusalem, Israel.

5Molecular Physiology and Therapeutics Branch National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland.

6Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany.

7Goldyne-Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel. axelrod@hadassah.org.il.