AMPK Activation Restores Salivary Function Following Radiation Treatment

Abstract

Head and neck cancers represent a significant portion of cancer diagnoses, with head and neck cancer incidence increasing in some parts of the world. 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, increased risk of developing oral mucositis, and malnutrition. There is currently no standard of care for radiation-induced salivary gland dysfunction, and treatment is often limited to palliative treatment that provides only temporary relief. Adenosine monophosphate (AMP)–activated protein kinase (AMPK) is an enzyme that activates catabolic processes and has been shown to influence the cell cycle, proliferation, and autophagy. In the present study, we found that radiation (IR) treatment decreases tissue levels of phosphorylated AMPK following radiation and decreases intracellular NAD+ and AMP while increasing intracellular adenosine triphosphate. Furthermore, expression of sirtuin 1 (SIRT1) and nicotinamide phosphoribosyl transferase (NAMPT) was lower 5 d following IR. Treatment with AMPK activators, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) and metformin, attenuated compensatory proliferation (days 6, 7, and 30) following IR and reversed chronic (day 30) salivary gland dysfunction post-IR. In addition, treatment with metformin or AICAR increased markers of apical/basolateral polarity (phosphorylated aPKCζT560-positive area) and differentiation (amylase-positive area) within irradiated parotid glands to levels similar to untreated controls. Taken together, these data suggest that AMPK may be a novel therapeutic target for treatment of radiation-induced salivary damage.

Metformin Attenuates TGF-β1-Induced Fibrosis in Salivary Gland: A Preliminary Study

“…Furthermore, clinical findings affirm that metformin administration results in a notable reduction in ovarian collagen tissue and fibrosis in postmenopausal patients diagnosed with T2DM [20]. In the context of radiation-induced salivary gland dysfunction, metformin demonstrates efficacy in curtailing compensatory proliferation and reinstating salivary flow rates to benchmarks observed in unirradiated controls [21]. Based on these insights, we posit metformin as a promising therapeutic candidate against salivary gland fibrosis.…”

Parotid glands have a dysregulated immune response following radiation therapy

“…Proliferation is an important component of the wound healing response; however, compensatory proliferation of the acinar compartment of parotid glands is a persistent phenotype that begins at day 5 after IR and continues through day 90 [ 35 ]. Several studies have reported that the elevated proliferative response in salivary glands is highly correlated with loss of function and treatments that restore salivary flow also attenuate compensatory proliferation of acinar cells [ 35 , 37 , 66 ]. Due to the fact that we did not observe an increase in neutrophil apoptosis, we postulate the parotid gland does not receive the necessary signals to transition from the inflammatory phase to the proliferative and regenerative phases, therefore contributing to the abnormal proliferative response and the lack of regeneration and restoration of function.…”

The Molecular Mechanisms in Senescent Cells Induced by Natural Aging and Ionizing Radiation

“…The expression of SIRT1 and NAMPT decreases 5 days after IR, with irradiation leading to decreased levels of phosphorylated AMPK in parotid gland tissues and decreased NAD+. Using AMPK activators resulted in a reduction in compensatory proliferation on days 6, 7, and 30 following IR, and it also reversed the chronic salivary gland dysfunction on day 30 that occurred after IR [ 192 ]. In a study by Liao et al [ 193 ], IR caused NAMPT activation 15–30 min after irradiation in human oral keratinocytes (HOKs) and HUVECs, which was probably a rapid stress response, and reduced nuclear NAD levels by 40–50%.…”