Cancer Biology Graduate Interdisciplinary Program, University of Arizona, Tucson, Arizona, United States of America.
Department of Nutritional Sciences, University of Arizona, Tucson, Arizona, United States of America.
PLoS One. 2019 Jul 9;14(7):e0219572. doi: 10.1371/journal.pone.0219572. eCollection 2019.
Radiotherapy is a common treatment option for head and neck cancer patients; however, the surrounding healthy salivary glands are often incidentally irradiated during the process. As a result, patients often experience persistent xerostomia and hyposalivation, which deceases their quality of life. Clinically, there is currently no standard of care available to restore salivary function. Repair of epithelial wounds involves cellular proliferation and establishment of polarity in order to regenerate the tissue. This process is partially mediated by protein kinase C zeta (PKCζ), an apical polarity regulator; however, its role following radiation damage is not completely understood. Using an in vivo radiation model, we show a significant decrease in active PKCζ in irradiated murine parotid glands, which correlates with increased proliferation that is sustained through 30 days post-irradiation. Additionally, salivary glands in PKCζ null mice show increased basal proliferation which radiation treatment did not further potentiate. Radiation damage also activates Jun N-terminal kinase (JNK), a proliferation-inducing mitogen-activated protein kinase normally inhibited by PKCζ. In both a PKCζ null mouse model and in primary salivary gland cell cultures treated with a PKCζ inhibitor, there was increased JNK activity and production of downstream proliferative transcripts. Collectively, these findings provide a potential molecular link by which PKCζ suppression following radiation damage promotes JNK activation and radiation-induced compensatory proliferation in the salivary gland.
放射治疗是头颈部癌症患者的常见治疗选择；然而，在这个过程中，周围健康的唾液腺经常会被意外照射。结果，患者经常会出现持续的口干和唾液分泌减少，从而降低他们的生活质量。临床上，目前还没有可用于恢复唾液功能的标准护理方法。上皮伤口的修复涉及细胞增殖和极性的建立，以再生组织。这个过程部分由蛋白激酶 C ζ（PKCζ）介导，PKCζ 是一种顶端极性调节剂；然而，其在辐射损伤后的作用尚不完全清楚。我们使用体内放射模型表明，在辐射后的小鼠腮腺中，活性 PKCζ 显著减少，这与持续到辐射后 30 天的增殖增加相关。此外，PKCζ 缺失小鼠的唾液腺显示出基础增殖增加，而辐射治疗并没有进一步增强这种增殖。放射损伤还会激活 Jun N-末端激酶（JNK），JNK 是一种增殖诱导的丝裂原激活蛋白激酶，通常被 PKCζ 抑制。在 PKCζ 缺失小鼠模型和用 PKCζ 抑制剂处理的原代唾液腺细胞培养物中，JNK 活性和下游增殖转录物的产生均增加。总之，这些发现提供了一个潜在的分子联系，即放射损伤后 PKCζ 的抑制促进了 JNK 的激活和唾液腺的放射诱导性代偿性增殖。
