Radiation-Induced Loss of Salivary Gland Function Is Driven by Cellular Senescence and Prevented by IL6 Modulation.

Yitzhak Marmary,Bruce J Baum,Carmit Orfaig-Geva,Jonathan H Axelrod,Stefan Rose-John,Svetlana Gaska,Lina Mizrachi,Eithan Galun,Annette Wygoda,Jonathan Cohen,Alexander Maly,Revital Adar,Ron Eliashar

doi:10.1158/0008-5472.can-15-1671

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.

Highlights

Radiotherapy has proven to be effective in treating a wide variety of human malignancies and is one of the most widely employed cancer therapy modalities
Persistent DNA damage and senescence in the salivary gland following irradiation To determine whether ionizing irradiation induces cellular senescence in salivary gland we irradiated mice with 13 Gy directed to the head and neck, a dose shown to produce profound glandular hypofunction [4, 27]
To further evaluate the hypothesis that cellular senescence is an inherent outcome of radiation-induced damage in the salivary gland, we examined irradiated glands for evidence of persistent DNA damage, one of the hallmarks of cellular senescence [20]

Summary

Introduction

Radiotherapy has proven to be effective in treating a wide variety of human malignancies and is one of the most widely employed cancer therapy modalities. Radiotherapy often generates severe side effects that can be devastating for the patient. For head and neck cancer, radiotherapy is currently one of the main treatment modalities for the roughly one-half million patients diagnosed each year worldwide [1,2,3]. This treatment achieves a 5-year survival rate of approximately 80% for early-stage and 35% for late-stage disease [1, 2]. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/)

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Conclusion