AMP-Activated Protein Kinase Activation Impacts Cell Proliferation and Salivary Flow Rates Following Radiation Therapy

Abstract

Head and neck cancers remain the sixth most common cancer worldwide and represent over 600,000 new cases diagnosed annually. Typical treatment of early-stage head and neck cancers includes either surgery or radiotherapy; however, advanced cases often require surgery followed by radiation and chemotherapy. Salivary gland damage following radiotherapy leads to severe and chronic hypofunction with decreased salivary output, xerostomia, impaired ability to chew and swallow, a greatly increased risk of developing oral mucositis, and malnutrition. There is currently no standard of care for radiation induced salivary gland dysfunction; treatment is often limited to palliative treatment that provides only temporary relief. AMP-activated protein kinase (AMPK) is an enzyme that activates catabolic processes and has been shown to influence the cell cycle, proliferation, and autophagy. Additionally, AMPK has been implicated in the cellular response to radiation. In the present study, we found that radiation (IR) decreased tissue levels of phosphorylated AMPK, as well as NAD+ and AMP. Further, expression of Sirtuin-1 and nicotinamide phosphoribosyl transferase (NAMPT) was lower five days following IR. Treatment with AMPK activator AICAR attenuated compensatory proliferation following IR, and both AICAR and Metformin treatment reversed chronic salivary gland dysfunction post-IR. Taken together, these data suggest that AMPK may be a novel therapeutic target for treatment of radiation-induced salivary damage.