Abstract
Annually, >600,000 new cases of head and neck cancer (HNC) are diagnosed worldwide with primary treatment being surgery and radiotherapy. During ionizing radiation (IR) treatment of HNC, healthy salivary glands are collaterally damaged, leading to loss of function that severely diminishes the quality of life for patients due to increased health complications, including oral infections and sores, cavities, and malnutrition, among others. Therapies for salivary hypofunction are ineffective and largely palliative, indicating a need for further research to uncover effective approaches to prevent or restore loss of salivary gland function following radiotherapy. Previous work in our lab implicated prostaglandin E2 (PGE2) as an inflammatory mediator whose release from radiation-exposed cells promotes salivary gland damage and loss of function. Deletion of the P2X7 purinergic receptor for extracellular ATP reduces PGE2 secretion in irradiated primary parotid gland cells, and salivary gland function is enhanced in irradiated P2X7R–/– mice compared to wild-type mice. However, the role of PGE2 signaling in irradiated salivary glands is unclear and understanding the mechanism of PGE2 action is a goal of this study. Results show that treatment of irradiated mice with the non-steroidal anti-inflammatory drug (NSAID) indomethacin, which reduces PGE2 production via inhibition of cyclooxygenase-1 (COX-1), improves salivary gland function compared to irradiated vehicle-treated mice. To define the signaling pathway whereby PGE2 induces salivary gland dysfunction, primary parotid gland cells treated with PGE2 have increased c-Jun N-terminal Kinase (JNK) activation and cell proliferation and reduced amylase levels and store-operated calcium entry (SOCE). The in vivo effects of blocking PGE2 production were also examined and irradiated mice receiving indomethacin injections have reduced JNK activity at 8 days post-irradiation and reduced proliferation and increased amylase levels at day 30, as compared to irradiated mice without indomethacin. Combined, these data suggest a mechanism whereby irradiation-induced PGE2 signaling to JNK blocks critical steps in saliva secretion manifested by a decrease in the quality (diminished amylase) and quantity (loss of calcium channel activity) of saliva, that can be restored with indomethacin. These findings encourage further attempts evaluating indomethacin as a viable therapeutic option to prevent damage to salivary glands caused by irradiation of HNC in humans.
Highlights
Each year, >600,000 new cases of head and neck cancer (HNC) are diagnosed across the world (Johnson et al, 2020)
We have previously shown that there are elevated levels of prostaglandin E2 (PGE2) secreted from primary parotid gland cells following IR exposure, with lower PGE2 levels detected in IR-exposed P2X7 receptor (P2X7R)−/− cells that correlate with improved salivary gland function (Gilman et al, 2019)
Indomethacin is an non-steroidal anti-inflammatory drug (NSAID) that inhibits both COX-1 and COX-2 functions, but COX-1 has a 10-fold lower IC50 value for indomethacin than COX-2 (COX-1 IC50: 13 nM; COX-2 IC50: 130 nM) (Warner et al, 1999). These findings are consistent with our data from primary parotid gland cells, where 25 μM indomethacin caused a significant reduction in COX-1 activity after 24 h but had no effect on COX-2 activity (Figure 2A)
Summary
Each year, >600,000 new cases of head and neck cancer (HNC) are diagnosed across the world (Johnson et al, 2020). Research suggests that interleukin (IL)-6 mediates induction of cellular senescence in irradiated (13 Gy) submandibular glands (SMGs), with elevated levels seen at 3 h and 14 days post-IR Both IL-6 knockdown and IL-6 treatment prior to radiation exposure unexpectedly protected SMGs from senescence at 8 weeks post-IR, leaving the role of IL-6 during the inflammatory response to radiation difficult to understand (Marmary et al, 2016). Another study demonstrated that there is a decrease in immune-related gene expression and reduced macrophage numbers in irradiated (15 Gy) SMGs at days 7–28 post-IR, whereas adenoviral-induced activation of the Sonic hedgehog (Shh) pathway at day 3 postIR increased immune gene expression and macrophage numbers (Zhao et al, 2020) These studies suggest that an effective therapy to prevent salivary gland dysfunction due to radiation should target the hemostasis/inflammation phase of tissue damage, i.e., 0–3 days post-IR
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
