P75NTR promotes radiation-induced submandibular gland epithelial cell apoptosis via the ceramide signaling.

OBJECTIVE

Radiotherapy for head and neck cancers often damages normal tissues, including radiation-induced sialadenitis. The role of the p75 neurotrophin receptor (p75NTR) in radiation injury is dual; however, its mechanisms in salivary glands are unclear. This study examines p75NTR's role in radiation-induced submandibular gland injury.

DESIGN

Acinar-like human salivary gland epithelial cells (HSG-AZA3) were irradiated after p75NTR overexpression (oe-p75NTR) or knockdown (sh-p75NTR). We assessed apoptosis, ceramide levels, oxidative stress, inflammatory factors, and apoptosis-related gene/protein expression. Additionally, we explored the impact of sh-p75NTR combined with the ceramidase inhibitor (Ceranib2) on irradiated HSG-AZA3 cells. Animal experiments evaluated the effects of sh-p75NTR and Ceranib2 on radiation damage to mouse mandibular glands.

RESULTS

Oe-p75NTR increased radiation-induced oxidative stress, inflammatory responses, and apoptosis, whereas sh-p75NTR offered protection by reducing these effects. Ceranib2 reversed sh-p75NTR's protective effects, increasing ceramide levels, oxidative stress, and apoptosis. In mice, sh-p75NTR protected against radiation-induced gland injury, while Ceranib2 diminished this protection and increased damage.

CONCLUSIONS

Interfering with p75NTR provides protection against radiation-induced salivary gland cell injury, while Ceranib2 negates this by boosting ceramide levels and promoting apoptosis. These findings suggest new molecular pathways involved in radiation-induced salivary gland injury and potential targets for developing radiation protection strategies.