School of Nutritional Sciences and Wellness, University of Arizona, Tucson, AZ, USA.
J Dent Res. 2023 May;102(5):546-554. doi: 10.1177/00220345221148983. Epub 2023 Feb 1.
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 aPKCζ-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.
头颈部癌症是癌症诊断的重要组成部分，在世界某些地区，头颈部癌症的发病率正在上升。早期头颈部癌症的典型治疗方法包括手术或放疗；然而，晚期病例通常需要手术加放疗和化疗。放疗后唾液腺损伤会导致严重和慢性功能减退，唾液分泌减少、口干、咀嚼和吞咽能力受损、口腔粘膜炎发生风险增加以及营养不良。目前，尚无针对放疗引起的唾液腺功能障碍的标准治疗方法，治疗通常限于姑息治疗，只能提供暂时缓解。一磷酸腺苷（AMP）激活的蛋白激酶（AMPK）是一种激活分解代谢过程的酶，已被证明可影响细胞周期、增殖和自噬。在本研究中，我们发现放疗（IR）治疗会降低放疗后组织中磷酸化 AMPK 的水平，并降低细胞内 NAD 和 AMP，同时增加细胞内三磷酸腺苷。此外，IR 后 5 天 SIRT1 和烟酰胺磷酸核糖转移酶（NAMPT）的表达降低。用 AMPK 激活剂 5-氨基咪唑-4-甲酰胺核苷酸（AICAR）和二甲双胍治疗可减轻 IR 后的代偿性增殖（第 6、7 和 30 天），并逆转 IR 后慢性（第 30 天）唾液腺功能障碍。此外，二甲双胍或 AICAR 治疗可增加辐射腮腺中顶端/基底外侧极性（磷酸化 aPKCζ阳性区域）和分化（淀粉酶阳性区域）的标志物，使其达到与未处理对照相似的水平。综上所述，这些数据表明 AMPK 可能是治疗放疗引起的唾液损伤的一种新的治疗靶点。
