Quinn Sierra N, Graves Sarai H, Dains-McGahee Clayton, Friedman Emilee M, Hassan Humma, Witkowski Piotr, Sabbatini Maria E
Department of Biological Sciences, Augusta University, Augusta, Georgia.
Division of Abdominal Organ Transplantation, Department of Surgery, Pancreatic Islet Transplant Program, The University of Chicago Medical Center, Chicago, Illinois.
Mol Carcinog. 2017 Apr;56(4):1344-1360. doi: 10.1002/mc.22598. Epub 2016 Dec 29.
Pancreatic cancer is one of the most lethal human malignancies. A better understanding of the intracellular mechanism of migration and invasion is urgently needed to develop treatment that will suppress metastases and improve overall survival. Cyclic adenosine monophosphate (cyclic AMP) is a second messenger that has shown to regulate migration and invasion of pancreatic cancer cells. The rise of cyclic AMP suppressed migration and invasion of pancreatic ductal adenocarcinoma cells. Cyclic AMP is formed from cytosolic ATP by the enzyme adenylyl cyclase (AC). There are ten isoforms of ACs; nine are anchored in the plasma membrane and one is soluble. What remains unknown is the extent to which the expression of transmembrane AC isoforms is both modified in pancreatic cancer and mediates the inhibitory effect of forskolin on cell motility. Using real-time PCR analysis, ADCY3 was found to be highly expressed in pancreatic tumor tissues, resulting in a constitutive increase in cyclic AMP levels. On the other hand, ADCY2 was down-regulated. Migration, invasion, and filopodia formation in two different pancreatic adenocarcinoma cell lines, HPAC and PANC-1 deficient in AC1 or AC3, were studied. We found that AC3, upon stimulation with forskolin, enhanced cyclic AMP levels and inhibited cell migration and invasion. Unlikely to be due to a cytotoxic effect, the inhibitory effects of forskolin involved the quick formation of AC3/adenylyl cyclase-associated protein 1 (CAP1)/G-actin complex, which inhibited filopodia formation and cell motility. Using Western blotting analysis, forskolin, through AC3 activation, caused phosphorylation of CREB, but not ERK. The effect of CREB phosphorylation is likely to be associated with long-term signaling changes. © 2016 Wiley Periodicals, Inc.
胰腺癌是最致命的人类恶性肿瘤之一。迫切需要更好地了解细胞内迁移和侵袭机制，以开发能够抑制转移并提高总体生存率的治疗方法。环磷酸腺苷（cAMP）是一种第二信使，已被证明可调节胰腺癌细胞的迁移和侵袭。cAMP水平升高可抑制胰腺导管腺癌细胞的迁移和侵袭。cAMP由细胞质中的ATP通过腺苷酸环化酶（AC）形成。AC有十种同工型；九种锚定在质膜上，一种是可溶性的。尚不清楚跨膜AC同工型的表达在胰腺癌中被修饰的程度以及介导福斯可林对细胞运动性的抑制作用的程度。通过实时PCR分析发现，ADCY3在胰腺肿瘤组织中高表达，导致cAMP水平持续升高。另一方面，ADCY2表达下调。研究了两种不同的缺乏AC1或AC3的胰腺腺癌细胞系HPAC和PANC-1中的迁移、侵袭和丝状伪足形成。我们发现，在用福斯可林刺激后，AC3可提高cAMP水平并抑制细胞迁移和侵袭。福斯可林的抑制作用不太可能是由于细胞毒性作用，它涉及AC3/腺苷酸环化酶相关蛋白1（CAP1）/G-肌动蛋白复合物的快速形成，从而抑制丝状伪足形成和细胞运动性。通过蛋白质印迹分析发现，福斯可林通过激活AC3导致CREB磷酸化，但不导致ERK磷酸化。CREB磷酸化的作用可能与长期信号变化有关。©2016威利期刊公司
