The University of Arizona, Cancer Biology Graduate Program, Tucson, AZ, 85721, USA.
The University of Arizona, Department of Nutritional Sciences, Tucson, AZ, 85721, USA.
Sci Rep. 2018 Apr 20;8(1):6347. doi: 10.1038/s41598-018-24678-4.
Xerostomia and salivary hypofunction often result as a consequence of radiation therapy for head and neck cancers, which are diagnosed in roughly 60,000 individuals every year in the U.S. Due to the lack of effective treatments for radiation-induced salivary hypofunction, stem cell-based therapies have been suggested to regenerate the irradiated salivary glands. Pharmacologically, restoration of salivary gland function has been accomplished in mice by administering IGF-1 shortly after radiation treatment, but it is not known if salivary stem and progenitor cells play a role. We show that radiation inactivates aPKCζ and promotes nuclear redistribution of Yap in a population of label-retaining cells in the acinar compartment of the parotid gland (PG)- which comprises a heterogeneous pool of salivary progenitors. Administration of IGF-1 post-radiation maintains activation of aPKCζ and partially rescues Yap's cellular localization in label retaining cells, while restoring salivary function. Finally, IGF-1 fails to restore saliva production in mice lacking aPKCζ, demonstrating the importance of the kinase as a potential therapeutic target.
口干症和唾液分泌功能减退症常因头颈部癌症的放射治疗而导致，美国每年约有 6 万人被诊断出患有这种癌症。由于缺乏针对放射性唾液腺功能减退症的有效治疗方法，因此有人提出基于干细胞的疗法来再生受辐射的唾液腺。在药理学上，通过在放射治疗后短时间内给予 IGF-1，已经在小鼠中实现了唾液腺功能的恢复，但尚不清楚唾液干细胞和祖细胞是否发挥了作用。我们发现，辐射会使 aPKCζ失活，并促进 Yap 在腮腺（PG）的腺泡腔内的标记保留细胞中的核重新分布 - 这包括一个异质的唾液祖细胞池。放射后给予 IGF-1 可维持 aPKCζ的激活，并部分挽救 Yap 在标记保留细胞中的细胞定位，同时恢复唾液功能。最后，IGF-1 未能恢复缺乏 aPKCζ的小鼠的唾液产生，这表明该激酶作为潜在的治疗靶点的重要性。
