Small Molecule APY606 Displays Extensive Antitumor Activity in Pancreatic Cancer via Impairing Ras-MAPK Signaling

• Published in: PloS one Vol. 11; no. 5; p. e0155874
• Main Authors: Guo, Na, Liu, Zuojia, Zhao, Wenjing, Wang, Erkang, Wang, Jin
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 25.05.2016; Public Library of Science (PLoS)
• Subjects: Activation; Anticancer properties; Antineoplastic agents; Antineoplastic Agents - pharmacology; Antitumor activity; Apoptosis; Apoptosis - drug effects; Bax protein; Bcl-2 protein; bcl-2-Associated X Protein - metabolism; Biology and Life Sciences; Cancer; Cancer therapies; Caspase; Caspase 3 - metabolism; Caspase-3; Cell culture; Cell cycle; Cell Line, Tumor; Cell migration; Cellular signal transduction; Chemistry; Chemotherapy; Cyclin A; Cyclin-dependent kinase; Cyclin-dependent kinase 2; Cytochrome; Cytochrome c; Cytochromes c - metabolism; Down-regulation; Downstream effects; Drug screening; Drug therapy; Genetic aspects; GTP; Guanosine triphosphate; Humans; Inhibition; Kinases; Laboratories; MAP kinase; MAP Kinase Signaling System - drug effects; Medical research; Medicine and Health Sciences; Membrane potential; Mitochondria; Mutation; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Physiological aspects; Physiology; Protein kinase; Proteins; Proto-Oncogene Proteins c-bcl-2 - metabolism; Proto-Oncogene Proteins p21(ras) - metabolism; Ras protein; Signal transduction; Signaling; Tumor cell lines; Tumorigenesis; United States; China; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0155874

Pancreatic cancer has been found with abnormal expression or mutation in Ras proteins. Oncogenic Ras activation exploits their extensive signaling reach to affect multiple cellular processes, in which the mitogen-activated protein kinase (MAPK) signaling exerts important roles in tumorigenesis. Therapies targeted Ras are thus of major benefit for pancreatic cancer. Although small molecule APY606 has been successfully picked out by virtual drug screening based on Ras target receptor, its in-depth mechanism remains to be elucidated. We herein assessed the antitumor activity of APY606 against human pancreatic cancer Capan-1 and SW1990 cell lines and explored the effect of Ras-MAPK and apoptosis-related signaling pathway on the activity of APY606. APY606 treatment resulted in a dose- and time-dependent inhibition of cancer cell viability. Additionally, APY606 exhibited strong antitumor activity, as evidenced not only by reduction in tumor cell invasion, migration and mitochondrial membrane potential but also by alteration in several apoptotic indexes. Furthermore, APY606 treatment directly inhibited Ras-GTP and the downstream activation of MAPK, which resulted in the down-regulation of anti-apoptotic protein Bcl-2, leading to the up-regulation of mitochondrial apoptosis pathway-related proteins (Bax, cytosolic Cytochrome c and Caspase 3) and of cyclin-dependent kinase 2 and Cyclin A, E. These data suggest that impairing Ras-MAPK signaling is a novel mechanism of action for APY606 during therapeutic intervention in pancreatic cancer.