Editors' ChoicePhysiology

Highlight: Understanding radiation sialadenitis

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Sci. Signal.  06 Jun 2017:
Vol. 10, Issue 482, eaan8666
DOI: 10.1126/scisignal.aan8666

A nonapoptotic function of caspase-3 underlies the salivary gland complications of radiation therapy of head and neck cancers.

Radiation therapy, using external beams or internally localized radioisotopes such as 131I, is frequently used to treat head and neck cancers. A major dose-limiting toxicity of these treatments, however, is damage-induced dysfunction of the salivary glands—radiation sialadenitis—resulting in pain, swelling, and difficulty swallowing. Although the involved glands eventually contain an inflammatory infiltrate and/or fibrotic replacement, particularly after high radiation doses, the basic pathophysiology underlying this complication has remained unclear. A paper from Ambudkar and colleagues has now revealed a large part of the underlying molecular mechanism. Under normal conditions, extracellular entry of Ca2+ into salivary acinar cells activates an ER-localized Ca2+ sensor protein, STIM1, to activate the store-operated Ca2+ channels TRPC1 and Orai1, thereby leading to fluid secretion. The authors showed that a different calcium-permeable nonselective ion channel, TRPM2, became activated by radiation and/or ROS, leading to an increase in mitochondrial Ca2+ which was accompanied by increased ROS production, loss of mitochondrial membrane potential, and release of active caspase-3. Caspase-3, in turn, cleaved STIM1 effectively disabling store-activated Ca2+ channels needed for fluid secretion. Mice in which TRPM2 had been knocked out were protected from radiation-induced dysfunction in store-operated Ca2+ channels, as were mice in which STIM1 expression in the salivary glands was restored after irradiation by adenoviral delivery of a STIM1 expression construct. The work identifies a number of potential therapeutic strategies: for example, drugs that inhibit TRPM2 or caspase-3, or targeted delivery of non-cleavable forms of STIM1, which could be used to alleviate the salivary gland complications of radiation therapy of head and neck cancers.

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