糖尿病引起的持续高血糖是胰腺癌（PC）的危险因素。我们之前曾报道过非典型蛋白激酶 C (aPKC) 的异常激活可增强 PC 细胞的进展。然而，目前尚无报道阐明高血糖是否促进PC细胞进展以及aPKC激活是否与PC细胞进展机制相关。我们研究了高血糖刺激是否加速PC细胞增殖、迁移和侵袭。此外，为了确定PC细胞是否在高糖刺激下激活aPKC，我们测量了PC细胞中aPKC在T560处的磷酸化。高糖刺激加速了PC细胞的增殖、迁移和侵袭。高葡萄糖处理增加了 PC 细胞中 aPKC 的激活形式，其中 T560 磷酸化。然而，aPKC 敲低减弱了这些效应。据报道，aPKC 通过 Yes 相关蛋白 (YAP) 激活诱导细胞转化。 YAP 表达在高葡萄糖处理的 PC 细胞中增加，但在 aPKC 敲低细胞中没有增加。 aPKC 与分区缺陷 3 (Par-3) 相互作用，后者有助于建立细胞极性并通过作为底物结合来抑制 aPKC。在 Par-3 敲低的 PC 细胞中，YAP 表达增加，与高葡萄糖处理无关。 Par-3 和 aPKC 显性负突变体的过度表达阻止了 YAP 的高葡萄糖刺激的核定位。 YAP 与锌指 E 盒结合同源盒 1 蛋白 (ZEB1) 形成复合物，ZEB1 是上皮间质转化的激活剂。高糖治疗或 Par-3 敲除可增加 ZEB1 表达，但 aPKC 敲除抑制了这种增加。高糖诱导的 aPKC 激活通过增强 YAP 信号通路促进 PC 进展。版权所有 © 2023 国际抗癌研究所（George J 博士） .Delinasios），保留所有权利。

Persistent hyperglycemia caused by diabetes mellitus is a risk factor for pancreatic cancer (PC). We have previously reported that aberrant activation of atypical protein kinase C (aPKC) enhances PC cell progression. However, no reports have elucidated whether hyperglycemia promotes PC cell progression and whether aPKC activation is related to PC cell progression mechanisms.We examined whether high-glucose stimulation accelerates PC cell proliferation, migration, and invasion. Furthermore, to determine whether PC cells activate aPKC upon high-glucose stimulation, we measured the phosphorylation of aPKC at T560 in PC cells.High-glucose stimulation accelerated PC cell proliferation, migration, and invasion. High-glucose treatment increased aPKC's activated form, with T560 phosphorylation, in PC cells. However, aPKC knockdown attenuated these effects. aPKC reportedly induces cell transformation through Yes-associated protein (YAP) activation. YAP expression was increased in high glucose-treated PC cells but not in aPKC-knockdown cells. aPKC interacts with partitioning defective 3 (Par-3), which aids in establishing cell polarity and inhibits aPKC by binding as a substrate. In Par-3-knockdown PC cells, YAP expression increased independently of high-glucose treatment. Over-expression of Par-3 and aPKC-dominant negative mutants prevented the high glucose-stimulated nuclear localization of YAP. YAP forms a complex with the zinc finger E-box binding homeobox 1 protein (ZEB1), an activator of epithelial-mesenchymal transition. ZEB1 expression was increased by high glucose treatment or Par-3 knockdown, but aPKC knockdown suppressed this increase.High glucose-induced aPKC activation promotes PC progression by enhancing the YAP signaling pathway.Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.