Research ArticlePhysiology

Radiation inhibits salivary gland function by promoting STIM1 cleavage by caspase-3 and loss of SOCE through a TRPM2-dependent pathway

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Sci. Signal.  06 Jun 2017:
Vol. 10, Issue 482, eaal4064
DOI: 10.1126/scisignal.aal4064

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Why radiation causes a dry mouth

Patients with head or neck cancers who receive radiation as part of their treatment frequently complain of dry mouth, an effect that is not due to cell death in salivary glands. Liu et al. found that the ion channel TRPM2, which is activated by radiation, suppressed a Ca2+ signaling pathway required for saliva production by triggering the cleavage and inactivation of a critical component of this pathway, the Ca2+ sensor STIM1. Overexpression of STIM1 in irradiated mice increased saliva production, suggesting that strategies that prevent the loss of STIM1 could prevent the dry mouth associated with irradiation.

Abstract

Store-operated Ca2+ entry (SOCE) is critical for salivary gland fluid secretion. We report that radiation treatment caused persistent salivary gland dysfunction by activating a TRPM2-dependent mitochondrial pathway, leading to caspase-3–mediated cleavage of stromal interaction molecule 1 (STIM1) and loss of SOCE. After irradiation, acinar cells from the submandibular glands of TRPM2+/+, but not those from TRPM2−/− mice, displayed an increase in the concentrations of mitochondrial Ca2+ and reactive oxygen species, a decrease in mitochondrial membrane potential, and activation of caspase-3, which was associated with a sustained decrease in STIM1 abundance and attenuation of SOCE. In a salivary gland cell line, silencing the mitochondrial Ca2+ uniporter or caspase-3 or treatment with inhibitors of TRPM2 or caspase-3 prevented irradiation-induced loss of STIM1 and SOCE. Expression of exogenous STIM1 in the salivary glands of irradiated mice increased SOCE and fluid secretion. We suggest that targeting the mechanisms underlying the loss of STIM1 would be a potentially useful approach for preserving salivary gland function after radiation therapy.

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