Wang Junli, Weng Sijia, Zhu Yue, Chen Hongmei, Pan Jueyu, Qiu Shuoyu, Liu Yufeng, Wei Dapeng, Zhu Tongbo
Department of Biochemistry, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, 3-17 Renmin South Road, Chengdu, 610041, Sichuan, People's Republic of China.
Department of Laboratory Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, Sichuan, People's Republic of China.
J Cell Commun Signal. 2023 Dec;17(4):1417-1433. doi: 10.1007/s12079-023-00780-9. Epub 2023 Aug 7.
An increasing number of studies have documented atypical protein kinase C isoform ι (PKCι) as an oncoprotein playing multifaceted roles in pancreatic carcinogenesis, including sustaining the transformed growth, prohibiting apoptosis, strengthening invasiveness, facilitating autophagy, as well as promoting the immunosuppressive tumor microenvironment of pancreatic tumors. In this study, we present novel evidence that PKCι overexpression increases STAT3 phosphorylation at the Y705 residue while decreasing STAT3 phosphorylation at the S727 residue in pancreatic cancer cells. We further demonstrate that STAT3 phosphorylation at Y705 and S727 residues is mutually antagonistic, and that STAT3 Y705 phosphorylation is positively related to the transcriptional activity of STAT3 in pancreatic cancer cells. Furthermore, we discover that PKCι inhibition attenuates STAT3 transcriptional activity via Y705 dephosphorylation, which appears to be resulted from enhanced phosphorylation of S727 in pancreatic cancer cells. Finally, we investigate and prove that by modulating the STAT3 activity, the PKCι inhibitor can synergistically enhance the antitumor effects of pharmacological STAT3 inhibitors or reverse the anti-apoptotic side effects incited by the MEK inhibitor, thereby posing as a prospective sensitizer in the treatment of pancreatic cancer cells.
越来越多的研究已证明非典型蛋白激酶C同工型ι（PKCι）是一种癌蛋白，在胰腺癌发生过程中发挥多方面作用，包括维持转化生长、抑制细胞凋亡、增强侵袭性、促进自噬以及促进胰腺肿瘤的免疫抑制性肿瘤微环境。在本研究中，我们提供了新的证据，即PKCι过表达会增加胰腺癌细胞中Y705位点的信号转导和转录激活因子3（STAT3）磷酸化水平，同时降低S727位点的STAT3磷酸化水平。我们进一步证明，Y705和S727位点的STAT3磷酸化相互拮抗，且胰腺癌细胞中Y705位点的STAT3磷酸化与STAT3的转录活性呈正相关。此外，我们发现PKCι抑制通过Y705去磷酸化减弱STAT3转录活性，这似乎是由于胰腺癌细胞中S727磷酸化增强所致。最后，我们研究并证明，通过调节STAT3活性，PKCι抑制剂可协同增强药理学STAT3抑制剂的抗肿瘤作用，或逆转MEK抑制剂引发的抗凋亡副作用，从而成为治疗胰腺癌细胞的一种有前景的增敏剂。
