Huang H-L, Wu H-Y, Chu P-C, Lai I-L, Huang P-H, Kulp S K, Pan S-L, Teng C-M, Chen C-S
The PhD Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
Oncogenesis. 2017 Jul 10;6(7):e359. doi: 10.1038/oncsis.2017.61.
MUC1-C overexpression has been associated with the progression of pancreatic tumors by promoting the aggressive and metastatic phenotypes. As MUC1 is a STAT3 target gene, STAT3 plays a major role in regulating MUC1-C expression. In this study, we report an alternative mechanism by which integrin-linked kinase (ILK) post-transcriptionally modulates the expression of MUC1-C by maintaining its protein stability in pancreatic cancer cells. We found that ILK acts in concert with STAT3 to facilitate IL-6-mediated upregulation of MUC1-C; ILK depletion was equally effective as STAT3 depletion in abolishing IL-6-induced MUC1-C overexpression without disturbing the phosphorylation or cellular distribution of STAT3. Conversely, ectopic expression of constitutively active ILK increased MUC1-C expression, though this increase was not noted with kinase-dead ILK. This finding suggests the requirement of the kinase activity of ILK in regulating MUC1-C stability, which was confirmed by using the ILK kinase inhibitor T315. Furthermore, our data suggest the involvement of protein kinase C (PKC)δ in mediating the suppressive effect of ILK inhibition on MUC1-C repression. For example, co-immunoprecipitation analysis indicated that ILK depletion-mediated MUC1-C phosphorylation was accompanied by increased phosphorylation of PKCδ at the activation loop Thr-507 and increased binding of PKCδ to MUC1-C. Conversely, ILK overexpression resulted in decreased PKCδ phosphorylation. From a mechanistic perspective, the present finding, together with our recent report that ILK controls the expression of oncogenic KRAS through a regulatory loop, underscores the pivotal role of ILK in promoting pancreatic cancer progression.
MUC1-C的过表达通过促进侵袭性和转移表型与胰腺肿瘤的进展相关。由于MUC1是STAT3的靶基因，STAT3在调节MUC1-C表达中起主要作用。在本研究中，我们报告了一种替代机制，即整合素连接激酶（ILK）通过维持其在胰腺癌细胞中的蛋白质稳定性来转录后调节MUC1-C的表达。我们发现ILK与STAT3协同作用以促进IL-6介导的MUC1-C上调；在消除IL-6诱导的MUC1-C过表达方面，ILK的缺失与STAT3的缺失同样有效，且不会干扰STAT3的磷酸化或细胞分布。相反，组成型活性ILK的异位表达增加了MUC1-C的表达，尽管激酶失活的ILK没有这种增加。这一发现表明ILK的激酶活性在调节MUC1-C稳定性方面是必需的，这通过使用ILK激酶抑制剂T315得到了证实。此外，我们的数据表明蛋白激酶C（PKC）δ参与介导ILK抑制对MUC1-C抑制的抑制作用。例如，免疫共沉淀分析表明，ILK缺失介导的MUC1-C磷酸化伴随着PKCδ在激活环Thr-507处磷酸化的增加以及PKCδ与MUC1-C结合的增加。相反，ILK过表达导致PKCδ磷酸化减少。从机制角度来看，本研究结果与我们最近的报告（即ILK通过一个调节环控制致癌KRAS的表达）一起，强调了ILK在促进胰腺癌进展中的关键作用。
